Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]([O:10][CH:11]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[CH:32]=[CH:31][C:15]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].CO.[OH-].[K+:42]>C1COCC1>[K+:42].[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][N:18]([C:16]([C:15]2[CH:31]=[CH:32][C:12]([CH:11]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:10][CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:3]([O-:4])=[O:2])=[CH:13][CH:14]=2)=[O:17])[CH2:19][CH2:20]1)=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: COC(=O)C(CC(C)C)OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)[O-]
Temperature: 70 °C

Procedure:
To a solution of tert-butyl 4-{4-[[1-(methoxycarbonyl)-3-methylbutoxy](phenyl)methyl]benzoyl}piperazine-1-carboxylate from step 3 (0.6 g, 1.1 mmol) in THF (6.5 mL) was added methanol (2.2 mL) and 1.0N aqueous potassium hydroxide solution (2.2 mL, 2.2 mmol). The mixture was heated at 70° C. for 20 minutes and then cooled down to room temperature. The crude mixture was evaporated under reduced pressure and co-evaporated twice with toluene. The solid residue obtained was used as such in the next step.
Reaction SMILES: [CH:1]([N:4]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23]CC)=[O:22])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[OH-].[K+].Cl>C(O)C>[CH:1]([N:4]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([OH:23])=[O:22])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(N(C(C)C)S(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(c1cccc(C(=O)O)c1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To ethyl 3-(N-isopropyl-3-(trifluoromethyl)phenylsulfonamido)benzoate (330 mg, 0.794 mmol) in ethanol (5 mL) was added 2 N KOH solution (2.4 mL). The mixture was stirred at room temperature for 3 days, and then 4 N HCl solution (1.3 mL) was added. The mixture was concentrated until the water was gone. Then dichloromethane/methanol (50:1, 50 mL) was added, the solution was filtered, and the filtrate was concentrated to give 3-(N-isopropyl-3-(trifluoromethyl)phenylsulfonamido)benzoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 (d, 6H, J=8 Hz), 4.62 (m, 1H), 7.30 (m, 1H), 7.45 (s, 1H), 7.60 (m, 1H), 7.80-8.10 (m, 5H), 13.18 (br s, 1H); MS (ESI) m/z 416 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:10][CH2:9][CH2:8][O:7]1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:6]2([C:4]([OH:5])=[O:3])[O:7][CH2:8][CH2:9][O:10]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1(c2ccc(Br)cc2)OCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccc(Br)cc2)OCCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
To a solution of 2-(4-Bromo-phenyl)-[1,3]dioxolane-2-carboxylic acid ethyl ester (example 346a), 300 mg) in tetrahydrofuran (2 mL) and water (2 mL) was added lithium hydroxide (41 mg) in two portions. The reaction mixture was stirred at room temperature over 2 days then concentrated in vacuo. The residue was acidified to pH=1 with aqueous hydrochloric acid solution (0.1N) extracted with ethyl acetate. The combined organic layer were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound as a colorless oil (225 mg; 66%). MS (ESI): m/z=271.1 [M−H]−.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:31]([O:30][C:28]([O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1)=[O:29])[CH3:32]
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)ON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.2 g (0.74 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide and 0.01 g (0.08 mmol) of 4-dimethylaminopyridine in 10 mL of dichloromethane and 0.29 g (3.7 mmol) of pyridine was added 0.28 g (2.6 mmol) of ethyl chloroformate dropwise. The resulting mixture was stirred at room temperature for 2 hours whereupon it was extracted with 20 mL of 1M aqueous HCl and a saturated solution of NaHCO3, then dried by sodium sulphate and filtered. The solvent was removed by evaporation under reduced pressure and the residue was crystallised from a mixture of dichloromethane and ethyl acetate to give white crystals of m.p. 188.9°-190° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[CH:21][CH:22]=[O:23])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2cccnc2c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc2cccnc2c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 7-quinolinecarboxaldehyde (prepared as described in J. Med. Chem. 1993, 36, 3308) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9]>CCO>[Cl:3][C:4]1[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)COc1ccc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(C(F)(F)F)cc1Cl

Procedure:
84 mL of 2 M aqueous NaOH was added to a solution of 23.97 g (0.084 mol) of ethyl (2-chloro-4-trifluoromethyl-phenoxy)-acetate in 200 mL EtOH and the mixture was refluxed for 1 hour. EtOH was concentrated by evaporation i. vac., the residue was diluted with ice water and acidified with 2 M aqueous HCl. The precipitate formed was filtered off, washed with water and dried at 70° C. i. vac.
Reaction SMILES: [CH2:1]([C:5]1[CH2:12][S:11][CH:10]2[N:7]([C:8](=[O:45])[CH:9]2[NH:13][C:14](=[O:44])[C:15](=[N:41][O:42][CH3:43])[C:16]2[N:17]=[C:18]([NH:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:19][CH:20]=2)[C:6]=1[C:46]([O:48]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:47])[C:2]([CH3:4])=[O:3].O>C(O)=O>[CH2:1]([C:5]1[CH2:12][S:11][CH:10]2[N:7]([C:8](=[O:45])[CH:9]2[NH:13][C:14](=[O:44])[C:15]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[N:41][O:42][CH3:43])[C:6]=1[C:46]([OH:48])=[O:47])[C:2]([CH3:4])=[O:3]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(C)=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CC(C)=O)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
A solution of the syn isomer of 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g) in formic acid (42 cc) is heated to 50° C. Distilled water (15 cc) is added in the course of 15 minutes and the mixture is stirred for 15 minutes at 50° C. It is filtered and the filtrate is concentrated to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 20° C. The residue is taken up 3 times in succession with ethanol (50 cc), which is evaporated off to dryness each time under reduced pressure (1 mm Hg; 0.13 kPa) at 20° C. The solid residue is recrystallised from propan-2-ol (60 cc) and the crystals are filtered off, washed with diethyl ether (20 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 30° C. This yields the syn isomer of 3-acetonyl-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.2 g) in the form of beige crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][CH:16]=[CH:15]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:16]=[CH:15]2
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]ccc2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(F)ccc3c2=O)cc1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
169 μL of p-methoxybenzylchloride (1.24 mmol, 1.1 eq) were added to a suspension of 200 mg of 6-fluoro-isoquinolinone (176) (1.13 mmol) and 368 mg of Cs2CO3 (1.36 mmol, 1.2 eq) in 3 mL of DMF. The mixture was stirred for 2 h and then poured on ice. The precipitate was filtered, washed with water and dried to yield 300 mg of the title compound. LCMS Method B, retention time 1.76 min, detected mass 284.14 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22].[S-:24][C:25]#[N:26].[K+]>CS(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][S:24][C:25]#[N:26])=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22]
Reactant: N#C[S-]
Reactant: CCCc1c(OCc2ccc(CBr)cc2)ccc(C(C)=O)c1O
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1c(OCc2ccc(CSC#N)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[2-Hydroxy-3-propyl-4-(4-bromomethylphenylmethoxy)phenyl]ethanone (6.4 g; 0.017 m) and potassium thiocyanate (3.3 g; 0.034 m) were dissolved in dry dimethylsulphoxide (60 ml) and stirred at room temperature for 4 hours. The solution was then poured onto water, stirred and filtered to give a white solid; dried at 60° C. under reduced pressure. Recrystallised from ethanol to give a white crystalline solid m.p. 110°-111° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]1[CH3:15].[C:17](Cl)(=[O:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[C:17]([C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]([CH3:15])[C:2]2([CH3:16])[CH3:1])=[CH:7][C:8]=1[CH3:12])(=[O:19])[CH3:18]
Reactant: Cc1ccc2c(c1)C(C)(C)CC(C)C2(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CC(C)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (21.0 g; 0.097 mol) and acetyl chloride (8.0 g; 0.102 mol) in dichloroethane (60 g), anhydrous aluminum chloride (14.9 g; 0.112 mol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with dilute hydrochloric acid. The organic layer was separated, washed with dilute hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution, dried and concentrated to give 7-acetyl-1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (19.3 g; 0.075 mol; 77%). B.P., 109° C./0.2 mmHg. M.P., 61.5°-62.5° C.
Reaction SMILES: [CH3:1]NCCN(C)C.C([Li])CCC.[CH:13]([Si:16]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([CH3:15])[CH3:14].CI>C1COCC1>[CH3:1][C:24]1[CH:25]=[C:18]([O:17][Si:16]([CH:13]([CH3:15])[CH3:14])([CH:26]([CH3:28])[CH3:27])[CH:29]([CH3:31])[CH3:30])[CH:19]=[CH:20][C:21]=1[CH:22]=[O:23]
Reactant: CNCCN(C)C
Reactant: CC(C)[Si](Oc1ccc(C=O)cc1)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1C=O
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of trimethylethylenediamine (0.45 mL, 3.48 mmol) in THF (9 mL) at −20° C. was added Butyllithium 1.6M in hexanes (2.11 mL, 3.8 mmol). The solution was stirred at −20° C. for 15 min. A solution of 4-Triisopropylsilanyloxy-benzaldehyde (0.922 g, 3.31 mmol) was added dropwise and the solution stirred for 15 min at −20° C. Bu 16M in hexanes (6.21 ml, 9.93 mmol) was added dropwise and the solution kept in the freezer at −20° C. for 26 hours. The solution was cooled to 40° C. and methyl iodide (3.71 mL, 59.60 mmol) was added. The solution was allowed to reach room temperature and further stirred 30 ml. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×30 mL). The combined extracts were dried (MgSO4), concentrated under vacuum and purified by column chromatography (silica gel, hexanes/Ethyl acetate 20:1, Rf0.085) (49%). 1H-NMR (CDCl3, 200.15 MHz): δ 10.1 (s, 1H), 7.69 (d, 1H, J=8.3), 6.80 (dd, 1H,J=8.6, 2.4), 6.72 (s, 1H), 0.61 (s, 3H), 1.33–1.19 (m, 3H), 1.12 (s,18H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:33])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:33])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:2][CH2:3]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCNCC2)cc1)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCN(C(=O)c3ccccc3)CC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and benzoyl chloride Rf value: 0.7 (silica gel, methylene chloride/methanol=10:1) C35H32N4O4
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10](O)(=O)/[CH:11]=[CH:12]\[C:13](O)=O>C(O)C.C(OCC)(=O)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:3](=[N:2][CH2:10][C:11]1[CH:8]=[CH:7][CH:6]=[CH:13][CH:12]=1)[CH2:4][CH3:5]
Reactant: CNCc1ccccc1
Reactant: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(=NCc1ccccc1)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The oily ethoxyiminium salt was combined with 7.6 mL (59 mmol) of methylbenzylamine in 70 mL of ethanol and stirred at room temperature 24 hours. It was then heated for 2 hours at 90°, cooled to 0°, and the solid amidine was filtered off. The solid was dissolved in ethyl acetate and 1 equivalent of maleic acid in ethyl acetate was added to yield 5.1 g of product as the maleate salt, mp 116-118.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C(C)c1ccc(Br)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 68b (5 g, 0.02 mol) in THF (100 mL) was added a 1 M THF solution of NaHMDS (22.6 mL, 22.6 mmol) at 0° C. under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then cooled to 0° C. and iodomethane (3.19 g, 22.5 mmol) was added dropwise. The ice-water bath was removed and stirring was continued for an additional hour at room temperature. The reaction mixture was then treated with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 68c as brown oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C11H13BrO2: 256.0 (M). found: 256.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](O)=[O:21])=[CH:12]1)[CH3:10].[F:23][CH2:24][CH2:25][NH2:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]([NH:26][CH2:25][CH2:24][F:23])=[O:21])=[CH:12]1)[CH3:10]
Reactant: NCCF
Reactant: CC(c1c(F)cccc1F)n1cc(C(=O)O)c2ncccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1c(F)cccc1F)n1cc(C(=O)NCCF)c2ncccc21
Reaction time: 0.08 h

Procedure:
See FIG. 16(a). 1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.090 g, 0.30 mmol), 2-fluoroethanamine (0.019 g, 0.30 mmol) and triethylamine (0.166 mL, 1.19 mmol) was taken in DCM (15 mL) under N2 and stirred. After 5 min, 1-Propanephosphonic acid cyclic anhydride (0.379 g, 1.19 mmol) was added. The resulting reaction was stirred at rt for 40 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water. DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product 1-(1-(2,6-difluorophenyl)ethyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.040 g, 38.7%) as a solid. ES+MS m/z: 348.40. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.05 (d, J=6.97 Hz, 3 H ) 3.67 (q, J=5.21 Hz, 1 H ) 3.71-3.82 (m, 1 H ) 4.49 (t, J=4.90 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 6.22 (q, J=7.16 Hz, 1 H ) 7.13 (t, J=8.57 Hz, 2 H ) 7.29 (dd, J=8.48, 4.71 Hz, 1 H ) 7.34-7.52 (m, 1 H ) 7.80 (d, J=8.29 Hz, 1 H ) 8.41 (s, 1 H ) 8.50 (d, J=4.71 Hz, 1 H) 8.92 (t, J=5.75 Hz, 1 H ).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)C3CCOCC3)nc12

Procedure:
From tetrahydro-pyran-4-yl-carboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 379 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.O[N:31]=[C:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[CH3:29][C:2]1([CH3:1])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:27][N:36]=[C:32]([CH:33]([CH3:35])[CH3:34])[N:31]=3)[CH2:11]2)=[O:9])[CH2:3]1
Reactant: CC(C)C(N)=NO
Reactant: CC1(C)CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCO1
Product: CC(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOC(C)(C)C3)C2)n1

Procedure:
250 mg (0.410 mmol, 68% pure) of 1-[(2,2-dimethylmorpholin-4-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 208A) and 46.1 mg (0.451 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 118 mg (59% of theory).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.[CH3:18][O:19][C:20](=O)[O:21]C>O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][C:20]([O:19][CH3:18])=[O:21])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)c1ccc(O)cc1
Yield: 48.6 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with sodium hydride (3.5 g, 147 mmol). At 0 deg C., 100 mL of DMF was added slowly with stirring. To the stirred solvent were added 1-(4-hydroxyphenyl)ethanone (5 g, 36 mmol) and dimethylcarbonate (15.5 g, 170 mmol), stirred at room temperature overnight. The RM was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutants. The product was obtained as pale yellow oil (3.4 g, yield: 47.66%). MS (ESI, 120 eV): m/z=195 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.79-7.82 (d, 2H), 6.81-6.84 (d, 2H), 6.21 (br s, 1H), 3.90 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=O)=[CH:4][CH:3]=1.ClCl.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]=[CH:18][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:7]=1
Reactant: O=CCc1ccc(Br)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: ClCl
Solvent: ClCCl
Product: CCOC(=O)C=CCc1ccc(Br)cc1
Reaction time: 16 h

Procedure:
To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl(4-bromophenyl)acetate (Compound A) in 150 ml of CH2Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2 Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(OCCO)C>[NH:10]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[NH2:11]
Reactant: Cc1ccc(Cl)nc1
Reactant: NN
Solvent: CCOCCO
Solvent: O
Product: Cc1ccc(NN)nc1

Procedure:
1.0 g (7.8 mmol) 2-chloro-5-methylpyridine are stirred under reflux in 5.7 ml (5.9 g, 117.6 mmol) hydrazine hydrate for 12 h. 10 ml ethylene glycol monoethyl ether are added to the cooled reaction mixture and the solvent is then removed completely on a rotary evaporator. This working step is repeated twice, methylene chloride is then added to the residue, the precipitate is filtered off, the filtrate is concentrated in vacuo and the residue is dried in vacuo.