Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13](O)=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O:21][C:22]([C:24]1[N:25]([NH:29][CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1)=O)C=C.ClCCl.[O-]CC.[Na+].Cl>CN(C)C=O.C(O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][N:29]1[C:13](=[O:14])[C:12]([C:7]2[NH:6][C:5]3[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=3[S:9](=[O:11])(=[O:10])[N:8]=2)=[C:22]([OH:21])[C:24]2=[CH:28][CH:27]=[CH:26][N:25]12
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: C=CCOC(=O)c1cccn1NCCC(C)(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (Example 4b, 0.3 g, 0.819 mmol) was dissolved in N,N-dimethylformamide (4.1 mL). 1-(3,3-Dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 4c, 0.205 g, 0.819 mmol) was added followed by a 1.0 M solution of N,N-dicyclohexylcarbodiimide in dichloromethane (0.860 mL, 0.86 mmol). The mixture was stirred at 25° C. for 2 h. N,N-Dicyclohexylurea precipitation was visible at this point. The mixture was diluted with dichloromethane (5 mL) and filtered under reduced pressure. The filtrate was washed with 1.0 M aqueous hydrochloric acid solution (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (4.1 mL). A 21% solution of sodium ethoxide in ethanol (0.673 mL) was added and the mixture was stirred at 80° C. for 4 h. Additional sodium ethoxide in ethanol (0.673 mL) was added and the mixture was stirred at 80° C. for 4 h. Upon cooling to 25° C., the pH was adjusted to approximately 6 by the addition of 3.0 M aqueous hydrochloric acid solution. Immediate precipitation was observed. Methanol (3 mL) was added and the mixture was shaken vigorously. The solid was collected by vacuum filtration, rinsed with methanol (3×2 mL) and dried in vacuo for 16 h to afford the desired product, 1-(3,3-dimethyl-butyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (0.268 g, 0.67 mmol, 82% yield) as a white powder. LC-MS (ESI) calcd for C20H21IN4O4S, found 540.03, found 366.95 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[Cl:12].C(Cl)Cl.C(N([CH2:21][CH3:22])CC)C.O.[CH2:24]([OH:27])CC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([O:27][CH3:24])=[CH:7][C:2]=1[CH:21]=[CH2:22]
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1F
Reactant: CCN(CC)CC
Reactant: CCCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: ClCCl
Product: C=Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (13.0 g, 49.24 mmol), PdCl2(dppf).DCM (0.804 g, 0.98 mmol), potassium ethenyl(trifluoro)borate (7.88 g, 59.09 mmol) and triethylamine (6.87 mL, 49.24 mmol) in n-propanol (130 mL) was heated to reflux for 4 hours. The mixture was allowed to cool to room temperature and poured into water (500 mL). The mixture was extracted with DCM (2×300 mL) then the combined organic extracts were dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 1-2% ethyl acetate in hexane to give the title compound (7.8 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11](I)[CH:10]=[N:9]2)[CH2:4][O:3]1.C1COCC1.C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>>[CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)[CH:10]=[N:9]2)[CH2:4][O:3]1
Reactant: Cc1c(I)cnn1C[C@@H]1COC(C)(C)O1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C[C@@H]1COC(C)(C)O1
Reaction time: 1 h

Procedure:
To a solution of 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-iodo-5-methyl-1H-pyrazole (67.0 mg, 0.208 mmol) in THF (2 mL, 20 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (0.64 mL, 0.83 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.1704 mL, 1.040 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=322.21/323.20/324.22 (50/100/50) [MH+]. HPLC: tR=1.49 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([C@@H:40]([OH:42])[CH3:41])[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50](O)=[O:51])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:42][C@@H:40]([CH3:41])[C@H:9]([NH:8][C:50](=[O:51])[CH2:49][N:46]1[CH2:47][CH2:48][O:43][CH2:44][CH2:45]1)[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11]
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1ccc(C[C@H](NC(=O)[C@@H](N)[C@H](C)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@@H](NC(=O)CN2CCOCC2)[C@H](C)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To (2S,3S)-2-amino-3-hydroxy-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)butanamide TFA salt (0.207 mmol assumed) was added 2-morpholinoacetic acid (48.0 mg, 0.331 mmol), HATU (0.126 g, 0.331 mmol), and DMF (1 mL). The mixture was cooled to 0° C. and DIEA (0.177 mL, 0.104 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (25,35)-3-hydroxy-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)butanamide (80 mg, 63%) as a colorless solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][CH:8]=[CH:9][C:10]=2C(O)=O)[CH:6]=1.II.[Br:16]Br.[C:18]([OH:21])(=[O:20])C>BrBr>[Br:16][C:10]1[CH:9]=[CH:8][CH:7]=[C:5]2[C:4]=1[CH:3]=[CH:2][C:1]([C:18]([OH:21])=[O:20])=[CH:6]2
Reactant: CC(=O)O
Reactant: O=C(O)c1cccc2ccccc12
Reactant: BrBr
Agent: II
Product: O=C(O)c1ccc2c(Br)cccc2c1
Reaction time: 18 h

Procedure:
To naphthoic acid (50 g) (ex Aldrich) in glacial acetic acid at reflux was added a few drops of bromine (ex BDH) followed by iodine (0.5 g) (ex (BDH). Bromine (15 ml) was added dropwise over one hour. The mixture was cooled to 25° and stirred there for 18 hours. The resulting white precipitate was filtered, dissolved in hot water and treated with concentrated hydrochloric acid. The precipitate was filtered and dried (over phosphorus pentoxide (ex BDH) to give 5-bromo-2-napthoic acid (recrystallised from ethanol) (28 g). Melting point 261°-2°. NMR 1H:(DMSO,CDCl3), 8.60(1H,s), 8.00(5H,m), 7.40(1H,m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=O.[CH3:14]/[C:15](/[NH2:19])=[CH:16]\[C:17]#[N:18].[CH2:20]([CH:23]1[CH2:28][C:27](=[O:29])[CH2:26][C:25](=O)[CH2:24]1)[CH2:21][CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:26]3[C:27](=[O:29])[CH2:28][CH:23]([CH2:20][CH2:21][CH3:22])[CH2:24][C:25]=3[NH:19][C:15]([CH3:14])=[C:16]2[C:17]#[N:18])[CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: C/C(N)=C\C#N
Reactant: CCCC1CC(=O)CC(=O)C1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c(OCC)c1
Temperature: 0 °C

Procedure:
The title compound was prepared according to the method described in example 1b starting from 3-bromo-5-ethoxy-4-hydroxy-benzaldehyde (6 g), 3-aminocrotonitrile (2.01 g) and 5-propylcyclohexane-1,3-dione (3.8 g). The reaction mixture was cooled (0° C.) and the title compound was filtered off and washed with ethanol (cold). Yield: 6.3 g. MS-ESI: [M+H]+=445/447
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[I:8][C:9]1[CH:10]=[C:11]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)[CH:12]=[CH:13][CH:14]=1>CO.[OH-].[Na+].O>[I:8][C:9]1[CH:10]=[C:11]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[N:16]2[CH3:5])[CH:12]=[CH:13][CH:14]=1
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cccc(I)c3)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c2c(c(=O)n1-c1cccc(I)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
Dimethyl sulfate (0.6 mL, 6.3 mmol) was added to a mixture of (4S,7R)-2-(3-iodo-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 18; 1.62 g, 4.1 mmol) in methanol (10 mL) and 1 M NaOH (20 mL). The mixture was stirred at room temperature overnight and then further portions of dimethyl sulfate (0.6 mL, 6.3 mmol) were added immediately, after 2 h, and after 5 h. The mixture was stirred at room temperature over the weekend, and it was then diluted with water and extracted with ethyl acetate (2×125 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-90 column, eluting with 0-100% ethyl acetate/hexanes to give (4S,7R)-2-(3-iodo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (620 mg, 38%), as a white solid, (4S,7R)-2-(3-iodo-phenyl)-3-methoxy-7,8,8-trimethyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole (606 mg, 37%) as a yellow solid and unreacted starting material (140 mg, 9%). ES(+)-MS (M+H) 409.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[OH:12])[C:5]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:4][CH:3]=1.O.O.O.[C:24]([O-:27])(=O)[CH3:25].[Na+].C[C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1C(Cl)=O>O>[OH:12][C:10]1[CH:9]=[C:8]([S:13]([OH:16])(=[O:15])=[O:14])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:1][C:24]([C:25]1[C:31]([CH3:30])=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)=[O:27])=[CH:3][CH:4]=[C:5]2[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(O)c12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 16 g portion of 4-amino-5-hydroxy-1,7-naphthalenedisulfonic acid in 120 ml of water is adjusted to pH 7.2. A 7.6 g portion of sodium acetate trihydrate and 8.8 g of 2-methyl-5-nitrobenzoyl chloride are added with vigorous stirring. The mixture is stirred overnight at room temperature. The solid is then collected by filtration, washed with water, 80% ethanol, ethanol, ether and dried, giving 13.0 g of 5-hydroxy-4-(5-nitro-o-toluamido)-1,7-naphthalenedisulfonic acid, disodium salt.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[C:4]([CH3:23])[C:3]=1[CH3:24].[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]3)=[C:4]([CH3:23])[C:3]=2[CH3:24])=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c(Cl)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C#N)cc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Yield: 94.2 %

Procedure:
Heat a mixture of tert-butyl 1-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.5 g, 4.23 mmol), 4-cyanophenylboronic acid (932 mg, 6.34 mmol), Cs2CO3 (5.51 g, 16.9 mmol) and (SP-4-1)-bis[bis(1,1-dimethylethyl)(4-methoxyphenyl)phosphine-κP]dichloro-palladium (29 mg, 0.042 mmol) in a mixture of 1,4-dioxane (30 mL) and H2O (10 mL) under N2 at 90° C. overnight. Partition the reaction mixture between EtOAc and H2O with dissolved NaHCO3. Separate the layers, and extract the aqueous layer with EtOAc. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2) to provide the title compound as a yellow solid (1.68 g, 94%). ES/MS m/z 422.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C@H:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1.O>[OH:14][CH2:13][C@@H:12]([N:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[CH2:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(C[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(C[C@@H](CO)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
To a stirred solution of (S)-3-((benzyloxy)carbonyl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (compound 7-2, 6.07 mmol) in 30 mL of dry THF at −15° C. were successively added N-methylmorpholine (6.07 mmol), iso-butylchloroformate (6.07 mmol). After stirring for 5 min at −15° C., a solution of NaBH4 (689 mg, 18.21 mmol) in 2.73 mL of water were added at once. The reaction was stirred at −15° C. for 2 min, then hydrolyzed with water (30 mL). Extracted with EtOAc (×3), washed with water (×3), brine (×1), dried over sodium sulfate, filtered, concentrated. Purification by chromatography on silica gel column (hexane/EtOAc) to give 1.9 g of colorless oil, compound 7-3.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C@:5]1([CH:16]=[O:17])[CH2:7][C@H:6]1[C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].S(=O)(=O)(O)O>>[CH3:4][C@:5]1([C@H:16]([OH:17])[CH3:1])[CH2:7][C@H:6]1[C@H:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: C[C@@H](c1ccccc1)[C@@H]1C[C@]1(C)C=O
Reactant: C[Mg]Br
Agent: O=S(=O)(O)O
Product: C[C@@H](c1ccccc1)[C@@H]1C[C@]1(C)[C@@H](C)O
Reaction time: 1 h
Yield: 66.9 %

Procedure:
Under a nitrogen atmosphere, methyl magnesium bromide (0.97 mol/L, tetrahydrofuran solution, 8.5 ml, 8.25 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −10° C. (1S*,2S*)-1-Methyl-2-[(R*)-1-phenylethyl]cyclopropane carbaldehyde (1.03 g, 5.5 mmol) was placed into the dropping funnel, and added dropwise in 5 minutes with the temperature kept at −10° C. After stirring for 60 minutes, a 20% aqueous sulfuric acid solution (4.5 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). (R*)-1-[(1S*,2S*)-1-Methyl-2-((R*)-1-phenylethyl)cyclopropyl]ethanol (0.75 g, 3.68 mmol, 67% yield) was obtained as the main isomer, and (S*)-1-[(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl]ethanol (0.205 g, 1.0 mmol, 18% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]=[C:19]([CH2:23][CH2:24][C:25]([OH:27])=O)[C:18]1=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:29](Cl)CCl>>[CH2:1]([O:8][NH:9][C:25](=[O:27])[CH2:24][CH2:23][C:19]1[C:18](=[O:28])[N:17]([CH2:10][CH2:11][C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:29]=2)[CH2:22][CH2:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC1=CCCN(Cc2ccccc2)C1=O
Reactant: ClCCCl
Reactant: NOCc1ccccc1
Product: O=C(CCC1=CCCN(CCc2ccccc2)C1=O)NOCc1ccccc1
Yield: 75 %

Procedure:
Benzyloxyamine was added to organic solvent dissolving 30 mg of 3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid (0.15 mmol) prepared by above Example 12 in EDC. The resulting compound was purified by Silica gel column chromatography with ethylacetate/chloroform (1:1) solvent mixture as an eluant to give 41 mg of the title compound (g5) (yield: 75%).
Reaction SMILES: [O:1]=[C:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:5](=[O:6])[CH:4]=[C:3]1[CH3:11]>C(Cl)Cl>[CH3:10][C:8]1([CH3:9])[CH2:7][C:5](=[O:6])[CH2:4][C@@H:3]([CH3:11])[C:2]1=[O:1]
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Solvent: ClCCl
Product: C[C@@H]1CC(=O)CC(C)(C)C1=O

Procedure:
The water phase (190 liters + 5 liters of wash-water) is stirred out five times with 60 liters of methylene chloride each time. The solvent phase is separated, washed twice with 60 liters of water each time and concentrated to about 15 liters on a rotary evaporator. This concentrate is dehydrated with 1.5 kg of sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue (1755 g) is dissolved while hot in 6 liters of diisopropyl ether, decolourised with 80 g of active carbon, filtered over diatomaceous earth padding and rinsed with 1.8 liters of hot diisopropyl ether. From this solution, 2.6 liters of diisopropyl ether are distilled off at normal pressure, such that the product remains dissolved in a three-fold amount of diisopropyl ether. The product is crystallised overnight at 5° C, filtered off under suction, washed twice with 1500 ml of cold n-hexane each time and dried for 15 hours at 40° C under reduced pressure. This first crystallisation produces 1280 g of optically pure [6R]-2,2,6-trimethyl-1,4-cyclohexanedione of melting point 91°-92° C. The mother liquor contains a further 447 g of substances. The latter is taken up in the same amount of n-hexane, treated with diisopropyl ether until the solution is clear, crystallised overnight at 5° C, filtered off under suction and washed twice with a small amount of cold n-hexane. The crystallisate is dried at 40° C under reduced pressure. This second crystallisation produces 83.6 g of product with a melting point of 70°-88° C. After triple recrystallisation with the three-fold amount of diisopropyl ether, there are obtained a further 43 g of optically pure [6R]- 2,2,6-trimethyl-1,4-cyclohexanedione of melting point 90.5°-91.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Li+].[CH2:24](I)[CH2:25][CH3:26]>>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:24][CH2:25][CH3:26])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCI
Reactant: O=c1nc(Nc2ccc([N+](=O)[O-])cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc([N+](=O)[O-])cc2)sc2ncccc2c1=O
Yield: 58.7 %

Procedure:
The reaction procedure of Example 11 was followed except that 901 mg (3.0 mmol) of 2-(4-nitroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 30 mg of lithium hydride and 612 mg of propyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 603 mg of 2,3-dihydro-2-[(4-nitrophenyl)imino]-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (59%, recrystallized from a mixture of ether and ethanol).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:22]([O-])([OH:24])=[O:23].O>S(=O)(=O)(O)O>[N+:22]([C:11]1[CH:10]=[C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:20])([F:21])[F:1])[CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
To a solution of 63.2 g (0.20 mole) of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid in 160 ml of concentrated sulfuric acid is added 40 ml of fuming nitric acid (90%) dropwise with stirring at 0°-5°. Following the nitric acid addition the solution is allowed to warm to 20° with stirring over a 1-hour period. The solutionis then added to a mixture of ice and water and allowed to stand for 18 hours. A precipitate results and is filtered, washed with water and dissolved in ether to obtain a solution which is washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated to give a residual solid. The residual solid is recrystallized from chlorobutane to give 40 g of 2-nitro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid having a melting point of 115°-116°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[C:13]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1(C)CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 1-benzyloxycarbonyl-4-oxopyrrolidine-3-carboxylate (1.0 g, 3.4 mmol) in acetone (30 mL), potassium carbonate (0.95 g, 6.9 mmol) and methyl iodide (1 mL) were added, and the mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the concentrate. The mixture was extracted with ethyl acetate (20 mL×3). The extract was washed with 10% aqueous solution of sodium thiosulfate (20 mL) and saturated aqueous solution of sodium chloride (20 mL) in this order, and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 4:1) to obtain 1.0 g (95%) of the title compound as a pale yellow oily product.