Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[C:17]([N:19]2[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])[CH2:20]2)[CH:16]=[C:15](Cl)[N:14]=1.[C:39]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=1[F:50])#[N:40].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[C:17]([N:19]2[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])[CH2:20]2)[CH:16]=[C:15]([C:44]2[CH:45]=[CH:46][C:41]([C:39]#[N:40])=[C:42]([F:50])[CH:43]=2)[N:14]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: COc1ccc(CNc2nc(Cl)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
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: C1COCCO1
Product: COc1ccc(CNc2nc(-c3ccc(C#N)c(F)c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To cis-1-[2-({[2,4-bis(methyloxy)phenyl]methyl}amino)-6-chloro-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (322 mg, 0.58 mmol) and (4-cyano-3-fluorophenyl)boronic acid (124 mg, 0.75 mmol) were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL), and the resulting mixture was purged (“degassed”) with N2 into a sealable tube for 5 minutes. Pd(Ph3P)4 (33.5 mg, 0.029 mmol) was added, and N2 gas was bubbled through the mixture for an additional 5 minutes. The tube was sealed, and the reaction mixture was stirred overnight at 100° C. The reaction mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc/Hexanes) afforded the title compound (305 mg) as a yellow foam. LC-MS (ES) m/z=641 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:13]([OH:20])[CH2:14]OS(C)(=O)=O.[Cl-].[Na+].S(=O)(=O)(O)O>O1CCCC1>[C:22]1([CH2:21][C@@H:12]([C@H:13]2[CH2:14][O:20]2)[N:3]2[C:4](=[O:11])[C:5]3=[CH:6][CH:7]=[CH:8][CH:9]=[C:10]3[C:2]2=[O:1])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OC[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)[C@H]1CO1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
A solution of 0.26 g of methanesulfonic acid (2S,3S)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2-hydroxy-4-phenylbutyl ester in 1.6 ml of tetrahydrofuran is treated at -15° with a solution of 0.090 g of potassium tertbutylate in 0.5 ml of tetrahydrofuran and the mixture is stirred for 0.5 hours. The mixture is treated with 2.2 ml of semi-saturated sodium chloride solution and the pH value is adjusted to 6 with 0.1 ml of 1N sulphuric acid. Thereafter, the mixture is extracted with ethyl acetate. The extracts are dried and filtered, and the filtrate is evaporated to give 0.12 g (60%) of 2(S)-[2-phenyl-1(S)-phthalimidoethyl]oxirane, IR (KBr): 1773m and 1709s (C=O of imide).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[CH:17]=[C:16]([C:28]([O:30]CC)=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].[OH-].[Li+].Cl>O1CCCC1.CO.O>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[CH:17]=[C:16]([C:28]([OH:30])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)C(C)C)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3[C@H](CO)C(C)C)cn1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 110, 213 mg, 0.35 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2 M lithium hydroxide (0.259 mL, 0.52 mmol). The reaction mixture was heated at 100° C. for 15 min in a microwave reactor. The reaction mixture was cooled to room temperature, diluted with water, and treated with 1 N HCl until pH 3-4. The precipitate that formed was collected by filtration, washed with water and hexanes. Purification via reverse phase HPLC (C18, acetonitrile/water 0-95% gradient) provided (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (146.4 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([OH:27])[CH2:10]1.[F:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:30][CH2:29][F:28])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=2)[C:12](=[O:26])[CH:11]([OH:27])[CH2:10]1
Reactant: FCCI
Reactant: O=C1C(O)CC(c2c(O)cccc2F)N1Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(O)CC(c2c(F)cccc2OCCF)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of rac-(3R*,5S*)-5-(2-fluoro-6-hydroxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (50 mg; 0.13 mmol), 1-fluoro-2-iodoethane (23 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (1.3 ml) was stirred at rt, under nitrogen, for 72 h. Filtration of the reaction mixture, and subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 431.96 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:23][C:24](=O)[CH:25]=[C:26]1[CH2:31][CH:30]([CH2:32][CH3:33])[CH2:29][CH2:28][C:27]1=O)C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[C:27]2[C:26]([CH2:31][CH:30]([CH2:32][CH3:33])[CH2:29][CH:28]=2)=[CH:25][C:24]1=[O:23]
Reactant: CCOC(=O)C=C1CC(CC)CCC1=O
Reactant: Cc1cccc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1CC=C2C(=CC(=O)N2c2c(C)cccc2Cl)C1
Temperature: 22 °C

Procedure:
3.45 g of 2-Chloro-6-methyl-aniline are dissolved in 26 ml of toluene. 0.227 g of p-toluene-sulfonic acid (mono hydrate) are added and the mixture is heated to reflux. A solution of 5.0 g of (5-Ethyl-2-oxo-cyclohexylidene)-acetic acid ethyl ester in 13 ml of toluene is added drop-wise during 75 minutes and the water formed is collected by the means of a water separator. The reaction mixture is heated to reflux for 15 hours, during which time the condensing solvent is frequently removed and replaced by fresh toluene. For work-up, the mixture is cooled to 22° C. and is treated with 70 ml of saturated aqueous sodium bicarbonate solution under rigorous stirring. The layers are separated and the toluene phase is washed with a 5% aqueous solution of citric acid and finally with a 10% solution of sodium chloride in water. The aqueous phases are extracted with 70 ml of toluene and the toluene phases are combined. The solvent is evaporated in vacuo to yield 7.1 g of the crude product as a highly viscous oil. An analytical sample of the crude product can be purified by chromatography on silica gel using toluene/ethyl acetate (9:1) as eluent to yield pure 1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one.
Reaction SMILES: C([O:9][CH:10]([C:27]([NH:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])=[O:28])[C@@H:11]([NH:16]C(OCC1C=CC=CC=1)=O)[CH2:12][CH2:13][CH2:14][CH3:15])(=O)C1C=CC=CC=1.[OH-].[Na+]>O1CCOCC1.O>[NH2:16][C@@H:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]([OH:9])[C:27]([NH:29][C@@H:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:31])=[O:28]
Reactant: CCCC[C@H](NC(=O)OCc1ccccc1)C(OC(=O)c1ccccc1)C(=O)N[C@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC[C@H](N)C(O)C(=O)N[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of 8.75 g (17.4 mmol) of (2S)-2-{[(benzyloxy)carbonyl]amino}-1-({[(1R)-1-phenylethyl]amino}carbonyl)hexyl benzoate and 6.97 g (174 mmol) of sodium hydroxide in 175 mL of dioxane and 75 mL of water was heated at reflux for 3 h. Upon cooling to room temperature, the reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over potassium carbonate and concentrated to afford 4.38 g (95%) of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=8 Hz, 1H), 7.39-7.20 (m, 5H), 4.99 (m, 1H), 4.51 (br s, 1H), 3.71 (d, J=3 Hz, 1H), 2.81 (m, 1H), 1.50-1.05 (m, 9H), 0.87 (t, 3H). ES-LCMS m/z 265 (M+H).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>ClCCl>[C:4]([O:3][C:1]([NH:2][C:11]([OH:12])([C:13]([F:16])([F:15])[F:14])[C:10]([F:18])([F:17])[F:9])=[O:8])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(O)(C(F)(F)F)C(F)(F)F

Procedure:
The 2-tert-butoxy-4,4-bis(trifluoromethyl)-1,3-oxazabuta-1 ,3-diene of formula II can be obtained by the method described by Steglich et al., Chemische Berichte 107:1488 (1974). The starting materials are tert-butyl carbamate ((CH3)3C—O—CO—NH2) and anhydrous hexafluoroacetone, which are initially reacted, for example, in a solvent such as dichloromethane at room temperature, to give 2-tert-butoxycarbonylamino-2-hydroxy-1,1,1,3,3,3-hexafluoropropane. This intermediate is then converted, for example, in a solvent such as diethyl ether at temperatures from about 0° C. to about 10° C., by treatment with trifluoroacetic anhydride in the presence of a base (e.g., quinoline), into the compound of formula II, which can be purified by distillation. Details of the preparation are described below.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>C1COCC1>[C:12]([O:11][C:10]([NH:9][C@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[C:2]1=[O:1])=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CCN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
To a round bottom flask was added (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (500 mg, 2.19 mmol), THF (10 mL) and a 6 M solution of LiHMDS in THF (0.475 mL, 2.85 mmol). The reaction was stirred at rt for 1 hr before it was cooled to 0° C. Then, methyl acrylate (0.237 mL, 2.63 mmol) was added to the reaction and the reaction was slowly warmed up to rt and stirred at rt overnight. The reaction was concentrated and purified using RP prep-HPLC (Method A) to give (S)-methyl 3-(3-(tert-butoxycarbonylamino)-2-oxoazepan-1-yl)propanoate (140 mg, 0.445 mmol, 20.3% yield) as a white solid. Anal. Calcd. for C15H26N2O5 m/z 314.3. found: 315.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 5.96 (d, J=5.5 Hz, 1H), 4.34 (dd, J=11.0, 6.0 Hz, 1H), 3.77 (ddd, J=13.6, 6.7, 6.6 Hz, 1H), 3.69 (s, 3H), 3.61 (ddd, J=13.9, 7.1, 7.0 Hz, 1H), 3.57-3.47 (m, 1H), 3.33 (dd, J=14.8, 4.4 Hz, 1H), 2.65-2.50 (m, 2H), 2.04 (d, J=13.2 Hz, 1H), 1.94 (d, J=13.7 Hz, 1H), 1.88-1.74 (m, 2H), 1.50-1.40 (m, 9H), 1.41-1.25 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 173.15, 172.24, 155.16, 79.35, 53.34, 51.80, 49.88, 45.50, 32.51, 28.39, 27.86, 27.74.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[CH3:22][C:23]([C:26]1[N:27]=[C:28]([NH2:31])[S:29][CH:30]=1)([CH3:25])[CH3:24]>>[CH3:22][C:23]([C:26]1[N:27]=[C:28]([NH:31][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:19])[S:29][CH:30]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2nc(C(C)(C)C)cs2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 33 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 4-(1,1-dimethyl-ethyl)-2-thiazolamine with a yield of 33% of theory.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[N:13][CH:12]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].CCO>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[C:4]([C:11]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[N:13][CH:12]=1)=[CH:3][CH:2]=[N:7]2
Reactant: Clc1cc(-c2cncc3ccccc23)c2nccn2n1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1ccc2c(-c3ccnn4ccnc34)cncc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
A pressure bottle charged with a mixture of 4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)isoquinoline (270 mg, 0.962 mmol), ammonium formate (243 mg, 3.85 mmol), palladium hydroxide on carbon (67 mg, 0.1 mmol) (20% wet), and EtOH (5 ml). The pressure bottle charged with a mixture of 4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)isoquinoline (270 mg, 0.962 mmol), ammonium formate (243 mg, 3.85 mmol), palladium hydroxide on carbon (67 mg, 0.1 mmol) (20% wet), and EtOH (5 ml) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 50° C. for 20 min and cooled to room temperature. The reaction mixture was passed through a pad of CELITE® and washed with MeOH. The filtrate was concentrated and the residue was purified by BIOTAGE® (20-60% EtOAc/CH2Cl2, 1.5 L) to give the product (220 mg, 93%). LC/MS: Rt=0.54 min. LC/MS (Condition A): 247.17.
Reaction SMILES: C([O:4][C@H:5]([CH3:35])[C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[N:13]=1)=[O:7])(=O)C.O.[OH-].[Na+]>CO>[C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)[N:13]=1)(=[O:7])[C@@H:5]([CH3:35])[OH:4]
Reactant: CC(=O)O[C@H](C)C(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](O)C(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To an ice-cooled mixture of 2-((2R)-2-acetoxypropionylamino)-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (2.1 g), water (4 ml) and methanol (17 ml) was added dropwise 1N sodium hydroxide solution (3 ml). After the addition had been completed, the reaction mixture was kept at 5° C. for 1 hour and allowed to warm to ambient temperature. After standing overnight at the same temperature, the reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (30:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with 70% ethanol to give white powder. Recrystallization from 70% ethanol gave 2-(D-lactoylamino)-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (1.13 g).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:12]=[C:11](F)[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:14])[CH:5]=1.[CH3:15][S-:16].[Na+]>CN(C)C=O>[F:14][C:6]1[C:7]([C:8]([OH:10])=[O:9])=[C:11]([S:16][CH3:15])[CH:12]=[C:4]([Br:3])[CH:5]=1
Reactant: C[S-]
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1cc(Br)cc(F)c1C(=O)O
Temperature: -12.5 °C
Reaction time: 0.21 h

Procedure:
To a 20 L flask was charged dimethyl formamide (14.5 L, 10.0 vol), followed by sodium hydroxide (293.7 g, 1.2 eq) and the reaction mass cooled to −15 to −10° C. 4-bromo-2,6-difluorobenzoic acid (1450 g, 1.0 equiv) was added over a period of 10-15 min at −15 to −10° C. and stirred for an additional 10-15 min. Sodium thiomethoxide (514.6 g, 1.2 equiv) was added over a period of 5-10 min at −10 to −5° C. On completion of the addition the temperature of the reaction was raised to 25-28° C. over a period of 45 to 60 min and maintained at that temperature 1.5-2 h. The temperature of the reaction was then raised to 60-65° C. over a period of 30-60 min and maintained at 60-65° C. for 5 h until the reaction was deemed complete. The reaction mixture was then cooled to 20-25° C. and quenched with a cooled (5-10° C.) solution of 2N HCl (5.045 L of 12N HCl in 30.3 L water). Following the quench, ethyl acetate (14.5 L, 10 vol) was added and the mixture stirred for 10-15 min. The phases were separated and the aqueous layer was extracted with ethyl acetate (7.25 L, 5 vol). The two phases were separated and the combined organic layer was washed with a brine solution (725 g of NaCl in 3.625 L of water). The phases were separated and the organic layer was washed with water (5.0 vol, 7.25 L). The phases were separated and the organic layer was dried over sodium sulfate (1450 g). The organic layer was filtered to remove the sodium sulfate, which was then washed with ethyl acetate (2.9 L, 2 vol). The organic layer was concentrated under reduced pressure at 45-50° C./30-40 mm Hg to ˜1 to 1.2 volumes and petroleum ether (7.25 L, 5 vol) was added at 40-45° C. over a period of 15-20 min. The solution was cooled to 20-25° C. over a period of 20-25 min. The solid was filtered and washed with petroleum ether (2.9 L, 2.0 vol) and the product dried under vacuum at 25-28° C., 0.4 to 0.7 mbar to afford 1410 g (87%, 99.40 Area %) of the intermediate 6-fluoro-4-bromo-2-methylsulfanyl-benzoic acid.
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[CH3:6][CH:7]([OH:10])[C:8]#[CH:9]>>[Br:1][C:2]1[CH:9]=[C:8]([CH:7]([OH:10])[CH3:6])[O:4][N:3]=1
Reactant: ON=C(Br)Br
Reactant: C#CC(C)O
Product: CC(O)c1cc(Br)no1

Procedure:
Reaction of dibromoformaldoxime with 3-butyn-2-ol gives 3-bromo-5-(1-hydroxyethyl)-isoxazole which is converted by oxidation into 3-bromo-5-acetylisoxazole, an intermediate for the preparation of 1-(3-bromoisoxazol-5-yl)-2-tert.butylamine-ethanol, a compound having broncodilating activity (European Patent No. 16255) known as Broxaterol.
Reaction SMILES: CO[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].[CH3:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14]>C1(C)C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH2:12][C:13](=[O:14])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 5 °C

Procedure:
118 g of oxalic acid dimethyl ester, warmed to 60° C., are added dropwise to a suspension of 59.4 g (1.1 mols) of sodium methylate in 200 g of toluene, cooled to 5° C., in the course of 1 hour, whilst stirring. 100 g (1 mol) of technical grade pinacolin are allowed to run rapidly into the mixture. The mixture is subsequently stirred for 15 minutes and 90 g of a methanol/toluene mixture are then distilled off, at boiling point760 : 67° to 100° C., over a packed column in the course of 3 hours. The bottom product is cooled to 40° C. and 258 g of 20.9% strength by weight aqeuous sulphuric acid are added. Phase separation is effected after thorough stirring for 1 hour. Distillation of the organic phase at boiling point0.4 : 75° C. gives 163.5 g of pivaloylpyruvic acid methyl ester (87.0% of the theoretical yield) with a purity of 99.0% (by analysis by gas chromatography).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:3].N1C=CC=CC=1.[F:29][C:30]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:31]=1[CH2:32][O:33][C:34]1[C:35]2[N:36]([C:40]([C:44]([NH:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:48]O)=[O:45])=[C:41]([CH3:43])[N:42]=2)[CH:37]=[CH:38][CH:39]=1.[OH-].[Na+]>ClCCl>[F:29][C:30]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:31]=1[CH2:32][O:33][C:34]1[C:35]2[N:36]([C:40]([C:44]([NH:46][C@@H:47]([CH2:50][CH2:51][CH2:52][CH:53]=[O:3])[CH3:48])=[O:45])=[C:41]([CH3:43])[N:42]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@H](C)CCCC=O
Temperature: -30 °C
Reaction time: 4 h

Procedure:
655 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane; 97%, Aldrich; 1.5 mmol) were initially charged in 10 ml of anhydrous dichloromethane and cooled to about −30° C. 83 μl (1.03 mmol) of pyridine and 430 mg 8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (1.03 mmol) in 20 ml of dichloromethane were added successively to this suspension. The reaction solution was warmed to room temperature and stirred for a further 4 h. With ice cooling, 1N aqueous sodium hydroxide solution was then added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered off and concentrated. The residue obtained was used without further purification for subsequent reactions.