Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH:23](O)[CH3:24])[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[N:14][CH:13]=4)[CH:23]([CH3:24])[CH2:22][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CC(C)O)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(C)N3c1cnc(N(C)C)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
To a solution of 1-[4-chloro-2-{[6-(dimethylamino)-4-methylpyridin-3-yl]amino}-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]propan-2-ol (Reference Example 94; 23 mg, 0.053 mmol) in pyridine (0.50 mL) was added methanesulfonyl chloride (0.012 mL, 0.160 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 5 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude mesylate was dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) and potassium carbonate (22 mg, 0.159 mmol) was added. The mixture was stirred at 50° C. for 4 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (15 mg, 0.036 mmol, 69%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][C:12]#[N:13].C(O)C.Cl>O>[F:1][C:2]1[C:3]2[S:11][C:12]([NH2:13])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: N#CSc1c(F)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1nc2cccc(F)c2s1
Yield: 29.7 %

Procedure:
A mixture of 1-fluoro-3-nitro-2-thiocyanatobenzene 2 (3.96 g, 0.02 mol), ethanol (30 mL), water (25 mL) and conc. hydrochloric acid (25 mL) was refluxed gently during the addition of hydrogen-reduced iron powder (8 g). After refluxing for 16 hr, the liquor was filtered hot, cooled, the residue filtered, dissolved in hot water, and neutralized with ammonia and then extracted with EtOAc to get the compound 7-fluorobenzo[d]thiazol-2-amine (1 g) as a colorless oil. LC-MS: m/z 169.2 (M+H)+
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)=O)=CC=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].[OH-].[Na+]>C1COCC1>[C:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCCOCCNC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl 4-methylbenzenesulfonate (5.00 g) in THF (40 mL) was added diethylamine (14.5 mL). The reaction mixture was stirred at room temperature overnight, and 1N aqueous sodium hydroxide solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.77 g).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][C:3]([C:6]([OH:8])=[O:7])([OH:5])[CH3:4].C(O)(=O)/C(=C\[C:15]([OH:17])=[O:16])/C.C(O)(=O)C(CC(O)=O)=C.C(C(O)=O)/C(/C(O)=O)=C\C(O)=O>>[C:1]([OH:10])(=[O:9])[CH2:2][C:3]([CH2:4][C:15]([OH:17])=[O:16])([C:6]([OH:8])=[O:7])[OH:5]
Reactant: C/C(=C/C(=O)O)C(=O)O
Reactant: CC(O)(CC(=O)O)C(=O)O
Agent: C=C(CC(=O)O)C(=O)O
Agent: O=C(O)/C=C(\CC(=O)O)C(=O)O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O
Yield: 47 %

Procedure:
Trans-aconitic acid, 17.4 g (0.10 mole) is dissolved in 300 mls of water. An excess of magnesium hydroxide, 25 g (0.43 mole), is added. This brings the pH to 9.0 and produces a mixture of the magnesium salt of trans-aconitic acid and free magnesium hydroxide. The resulting mixture is then stirred and heated for 6 hours in a Parr pressure reactor at a temperature of 170° C. The reaction mixture is then cooled, mixed with 143 g of 30% sulfuric acid solution and the resulting solution evaporated to dryness in vacuo. The evaporation residue is then extracted with 400 mls of acetone and the acetone extract filtered to remove MgSO4. The acetone filtrate is then evaporated to give 19 g of a residue containing 47% (47% yield) of citric acid, 9% citramalic acid, 5% citraconic acid, 10% itaconic acid, 12% trans-aconitic acid and the balance, water.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:4]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: O=C([O-])O
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2ccc(-c3nnnn3C)cc2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.2 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide (32 mg, 0.0524 mmol) in acetone (5 mL), sodium bicarbonate (45 mg, 0.6 mmol) and dimethyl sulfate (0.11 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (3 mg) and the other regioisomer (18 mg).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[C:9]1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.[C:32]([NH:35][CH2:36][CH2:37][NH2:38])(=[O:34])[CH3:33]>CS(C)=O>[O:25]([CH2:24][C:9]1[NH:8][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[C:16]([NH:38][CH2:37][CH2:36][NH:35][C:32](=[O:34])[CH3:33])[C:11]=2[CH:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)NCCN
Reactant: CC(C)(C)OC(=O)n1c(COc2ccccc2)cc2c(Cl)nc(-c3ccccc3)nc21
Solvent: CS(C)=O
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc2[nH]c(COc3ccccc3)cc12
Temperature: 100 °C
Yield: 90.9 %

Procedure:
A solution containing (8.1) (85 mg, 0.20 mmol), N-acetylethylene-diamine (201 mg, 1.95 mmol) and DMSO (3 mL) was heated to 100° C. After 1 h the temperature was raised to 130° C. After 3 h the reaction was cooled to room temperature and partitioned between EtOAc and water. The water layer was extracted with EtOAc (2×). The combined EtOAc layers are washed with water, dried over MgSO4, filtered and concentrated. Flash chromatography (SiO2; 1/10 EtOH/CHCl3, Rf 0.25) yielded 73 mg (93%) of a white foamy solid, mp. 196-197° C. 1H NMR (200 MHz, DMSO-d6): δ 1.79 (s, 3H), 3.36 (m, 2H), 3.61 (m, 2H), 5.12 (s, 2H), 6.59 (s, 1H), 6.89-7.09 (m, 3H), 7.20-7.50 (m, 5H), 7.57 (brt, 1H), 8.03 (brt, 1H), 8.39 (m, 2H), 11.81 (br s, 1H); MS (ES): 402.6 (MH+). tR (method A)=3.6 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].[CH3:19][O:20][C:21](=[O:34])[C@H:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[C:27]([F:33])[CH:26]=1)[CH3:23].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:9]([C:8]2[C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])=[C:27]([F:33])[CH:26]=1)[CH3:23]
Reactant: COC(=O)[C@@H](C)Oc1ccc(CN)c(F)c1
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1

Procedure:
The compound of Formula (5.0.31) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(3-cyano-phenoxy)-nicotinic acid and (R)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid methyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.C(=O)([O-])O.[Na+].[C:17]([NH:25][C:26]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na].C(=O)([O-])O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[C:17]([NH:25][C:26]1[CH:38]=[C:37]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OB(O)c1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-c2c(F)cccc2Cl)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
83 mg of 2-chloro-6-fluorophenylboronic acid, 0.10 g of sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of wafer and 23 mg of tetrakis(triphenylphosphine)palladium(0) were added to 2.1 mL of toluene solution containing 0.15 g of tert-butyl 2-(benzamido)-4-bromobenzoate, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 21 mg of 2-chloro-6-fluorophenylboronic acid and 23 mg tetrakis(triphenylphosphine)palladium(0) were added and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, toluene and a saturated sodium, hydrogen carbonate aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=10:1] to obtain tert-butyl 2-(benzamido)-4-(2-chloro-6-fluorophenyl)benzoate.
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[C:13]2=[N:14][N:15]([CH2:23][CH2:24][CH3:25])[C:16]([CH2:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20])=[C:12]2[C:11]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[N:5]=1>[OH-].[Na+]>[NH2:3][C:4]1[C:13]2=[N:14][N:15]([CH2:23][CH2:24][CH3:25])[C:16]([CH2:17][C:18]([CH3:21])([CH3:22])[C:19]([NH2:20])=[O:1])=[C:12]2[C:11]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[N:5]=1
Reactant: OO
Reactant: CCCn1nc2c(N)nc3ncccc3c2c1CC(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Product: CCCn1nc2c(N)nc3ncccc3c2c1CC(C)(C)C(N)=O

Procedure:
Hydrogen peroxide (0.8 mL of 30%) was added to a suspension of 3-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2,2-dimethylpropanenitrile (0.54 g, 1.75 mmol) in 6 N aqueous sodium hydroxide. The reaction and work-up procedures described in Example 1288 were followed with the modification that the reaction was heated for 5.5 hours. Following chromatographic purification (eluting with 0% to 55% CMA in chloroform) and drying under high vacuum, 0.16 g of 3-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2,2-dimethylpropanamide was obtained as a white solid, mp 254-257° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[CH:4][C:3]=1[Cl:12].CN(C=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[Cl:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(Cl)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Sc1ccc(Br)c(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
4-Bromo-3-chloro-benzenesulfonyl chloride (3.78 g, 13.0 mmol) was dissolved in dichloromethane (40 ml) and DMF (1.0 ml) was added. The mixture was cooled to 0° C. under argon and triphenylphosphine (10.26 g, 39.0 mmol) was added slowly, then the mixture was allowed to return to room temperature with stirring over 16 h. Hydrochloric acid (1 M, 75 ml) was added and the layers were separated. The organic layer was concentrated and the residue suspended in 1 M aqueous sodium hydroxide (75 ml) and filtered. The filtrate was extracted with Et2O (×2), then neutralised (1 M HCl, 75 ml). The mixture was then extracted (Et2O×3) and the combined organic layers were dried (Na2SO4) and concentrated to afford the title compound as a colourless oil (0.94 g, 32%). 1H NMR (CDCl3 400 MHz) 3.49 (1H, s), 7.02 (1H, dd, J=8.35, 2.24 Hz), 7.38 (1H, d, J=2.18 Hz), 7.45 (1H, d, J=8.35 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH3:32])[CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCCN1CCOCC1
Product: CN(CCN1CCOCC1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(2-morpholin-4-yl-ethyl)-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and Methyl-(2-morpholin-4-yl-ethyl)-amine following General Procedure C.
Reaction SMILES: [Na].[O:2]([CH:9]([CH3:13])[C:10](=[O:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCO>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[O:20])[CH2:11][C:10](=[O:12])[CH:9]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:13])[CH3:19]
Reactant: CC(=O)C(C)Oc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)C(C)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
Sodium (82 mg, 3.55 mmol) was added to EtOH absolute (9.8 mL) at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then (rac)-3-phenoxy-butan-2-one (530 mg, 3.23 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes. Then diethyl oxalate (0.44 mL, 3.23 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent evaporated in vacuo. The residue was diluted with water, the mixture acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM 100%) to yield (rac)-2,4-dioxo-5-phenoxy-hexanoic acid ethyl ester (566 mg, 58% yield) as an orange oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH2:5]1>O>[CH3:3][C:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH:5]=1
Reactant: CC1CC=C(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into 1 liter reaction flask equipped with stirrer, thermometer reflux condenser and heating mantle is placed 100 ml anhydrous methyl, 1.25 moles (100 grams) of 50% aqueous NaOH solution, 100 ml water and 154 grams (1 mole) of the methyl ester of 4-methyl-cyclohexene-1-carboxylic acid. The reaction mass is stirred for a period of 5 hours at room temperature and then extracted with 1 volume of diethyl ether. The aqueous layer is set aside with 10% hydrochloric acid and extracted with diethyl ether. The diethyl ether extracts are washed with saturated sodium chloride solution and the ether is evaporated yielding 100.5 grams of solid melting at 95° C. This material is the carboxylic acid having the structure: ##STR42## as confirmed by NMR and IR analysis.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCBr)cc1
Temperature: 70 °C
Yield: 89.3 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (1.52 g, 10 mmol), 1,3-dibromo-propane (20.3 mL, 200 mmol) and potassium carbonate (4.2 g, 30 mmol) in 100 mL of dry CH3CN was heated at 70° C. for 5.0 hr. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite and rinsed with CH3CN. The combined filtrates were concentrated in vacuo and purified by ISCO (Hexane-ethyl acetate: 80:20 to 0:100) on silica gel to afford 107A (2.44 g, 89%) as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1.C1(N=C=N)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:35][CH2:36][C:37]([C:40]1[O:44][C:43]([C:45]2[CH:46]=[CH:47][C:48]([Cl:52])=[C:49]([OH:51])[CH:50]=2)=[C:42]([C:53]2[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=2)[CH:41]=1)([CH3:39])[CH3:38]>CN(C=O)C>[Cl:52][C:48]1[CH:47]=[CH:46][C:45]([C:43]2[O:44][C:40]([C:37]([CH3:39])([CH3:38])[CH2:36][NH:35][C:12]([CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][O:3][CH3:2])[CH2:11][CH2:10]3)=[O:14])=[CH:41][C:42]=2[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][CH:58]=2)=[CH:50][C:49]=1[OH:51]
Reactant: CC(C)(CN)c1cc(-c2ccncc2)c(-c2ccc(Cl)c(O)c2)o1
Reactant: COCCN1CCC(C(=O)O)CC1
Agent: Cl
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCC(C(=O)NCC(C)(C)c2cc(-c3ccncc3)c(-c3ccc(Cl)c(O)c3)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
A solution of the product of Example 4 Step 2 (265 mg, 1.18 mmol) in DMF (5 ml) was treated with N-cyclohexylcarbodiimide, N′-methyl polystyrene (1.8 g) and 1-hydroxybenzotriazole hydrate (162 mg, 1.19 mmol). The mixture was stirred at room temperature for 30 minutes and then treated with a solution of the product of Example 3 Step 2 (407 mg, 1.19 mmol) in DMF (2 ml). After stirring for a further 16 hours, the reaction mixture was applied to a Bond Elut SCX cartridge. The cartridge was eluted with methanol and then 0.880 ammonia solution/methanol (1:9) to elute the product. After concentrating in vacuo, the product was purified further by chromatography on silica gel eluting with chloroform/ethanol/0.880 ammonia solution (90:9:1) to yield the title compound (340 mg, 56%); MS (ES+) m/e 512, 514 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:37](C(=O)C)[C:38](=[O:40])[CH3:39])[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]([NH:37][C:4]1[NH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=3)[C:12]=2[F:28])=[O:8])=[C:2]([Cl:1])[N:3]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)N(C(C)=O)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 19.8 %

Procedure:
A solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(diacetylamino)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.047 g, 0.071 mmol) and TFA (0.5 mL, 6.5 mmol) in CH2Cl2 (1.0 mL) was stirred at RT overnight. The solution was concentrated and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) to provide the title compound (0.007 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (br. s., 1H) 11.52 (br. s., 1H) 8.81 (br. s., 1H) 7.82 (s, 1H) 7.51-7.55 (m, 2H) 7.50 (s, 1H) 7.47
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]([CH3:35])[S:30][C:31]=2[C:32](O)=[O:33])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]=[C:29]([CH3:35])[S:30][C:31]=2[C:32]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:33])=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1nc(-c2ccc(F)cc2)c(C(=O)O)s1
Product: Cc1nc(-c2ccc(F)cc2)c(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic Acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 4-(4-Fluoro-phenyl)-2-methyl-thiazole-5-carboxylic acid.
Reaction SMILES: C(OP([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(COCC)=O)C.[H-].[Na+].[Si:18]([O:25][CH2:26][CH2:27][CH2:28][CH:29]=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCCC=O
Reactant: CCOCP(=O)(CC(=O)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
Ethyl 2-(ethoxy(ethoxymethyl)phosphoryl)acetate (75.8 g, 0.3386 mol) was added to NaH (13.5 g, 60%) in 600 mL THF at 0° C., and the solution was warmed at RT for 1 hour, followed by the addition of 4-(tert-butyldimethylsilyloxy)butanal (5) (57.0 g, 0.2822 mol) in THF (200 mL) at 0° C., The mixture was stirred at RT for 2 hours. After removal of the solvent, the residue was dissolved in DCM, and the mixture was washed with water (3×200 mL) and brine (3×200 mL), dried over Na2SO4 and concentrated to give the desired compound of (E)-ethyl 6-(tert-butyldimethylsilyloxy)hex-2-enoate (7) (37.0 g, yield 48%) as yellow oil which was purified by column chromatography on silica gel (eluent: PE:EA=30:1). 1H NMR (300 MHz, CDCl3): δ 0.0021 (S, 6H), 0.0857 (S, 9H), 1.197 (t, 3H), 1.600 (m, 2H), 1.197 (t, 3H), 2.240 (q, 2H), 3.586 (t, 2H), 4.098 (q, 2H), 5.832 (d, J=15.6 Hz, 1H), 6.936-6.885 (m, 1H); LC-MS found 273 (M+H)+.