Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]([CH3:15])[C:3]=1[CH3:16].C1C(=O)N([Br:24])C(=O)C1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[S:6][C:5](=[N:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[N:4]([CH2:15][Br:24])[C:3]=1[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)sc(=NC(=O)OC(C)(C)C)n1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Cc1c(Br)sc(=NC(=O)OC(C)(C)C)n1CBr
Yield: 85.1 %

Procedure:
tert-Butyl (5-bromo-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)carbamate (2.9 g) obtained in Example 30b) was dissolved in 1,2-dichloroethane (50 mL). AIBN (0.1 g) and NBS (1.7 g) were added thereto at room temperature, and the mixture was mixed at 80° C. for 3 hours. The reaction solution was poured into an aqueous potassium carbonate solution. The mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give tert-butyl (5-bromo-3-bromomethyl-4-methyl-1,3-thiazol-2(3H)-ylidene)carbamate (3.1 g) as a brown oily matter. The resulting compound and 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.0 g) obtained in Example 3a) were dissolved in DMF (30 mL). Potassium carbonate (0.75 g) was added thereto and the mixture was mixed at 70° C. for 4 hours. The solvent was distilled off, and the residue was poured into water. The mixture was extracted with a mixed solution of chloroform-methanol, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (1.2 g) as a white powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12]/[CH:13]=[CH:14]/[CH2:15][C:16]([O:18]C)=[O:17])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+]>CO.O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12]/[CH:13]=[CH:14]/[CH2:15][C:16]([OH:18])=[O:17])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C/C=C/CC(=O)NCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C/C=C/CC(=O)NCCc1ccccc1
Yield: 83.4 %

Procedure:
The product of step (a) (13.9 g., 48 mmoles) and sodium bicarbonate (4.05 g., 48 mmoles) in methanol (300 ml) and water (60 ml) was heated at reflux for 8 hr. The solution was evaporated to dryness and the residue partitioned between water and ethyl acetate. The aqueous phase was separated, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. Evaporation of the organic extracts gave the sub-title compound (9.9 g) mp 101°-103°.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[S:4][NH:3]1.[N+](=[CH2:16])=[N-]>C(O)(C)C.CCOCC>[CH3:16][O:12][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[C:2](=[O:1])[NH:3][S:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(=O)[nH]sc2c1
Solvent: CCOCC
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)[nH]sc2c1
Reaction time: 0.17 h

Procedure:
A solution of 19.5 g (0.1 mole) of 3-oxo-1,2-benzisothiazoline-6-carboxylic acid in 40 ml of isopropanol is treated with an excess of a solution of diazomethane in ether added at 0° C. with stirring over a period of 10 minutes. The reaction mixture is evaporated to dryness and the 3-oxo-1,2-benzisothiazoline-6-carboxylic acid methyl ester is obtained as an oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5](=O)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>C(O)C.O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:5]([CH:6]=[CH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][C:3]([C:2]([F:17])([F:16])[F:1])=[N:28]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(C=Cc1ccccc1)CC(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C=Cc2ccccc2)cc1
Yield: 17.8 %

Procedure:
1,1,1-Trifluoro-6-phenylhex-5-ene-2,4-dione (2.28 mmol) and 4-methoxyphenylhydrazine hydrochloride (435 mg, 2.5 mmol) were heated in ethanol (7 mL) at 70° C. overnight. The solution was diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried over MgSO4 and concentrated. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave 0.14 g of the desired product, along with many mixed fractions. Only the clean fractions were carried on. LC-MS (C19H15F3N2O calculated 344) m/z 345 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.43-7.30 (m, 7H), 7.12 (d, J=16.2 Hz, 1H), 7.05-7.00 (m, 2H), 6.88 (s, 1H), 6.78 (d, J=16.2 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[CH:4]=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([C:3](=[CH:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1([CH3:14])[CH3:15])[CH2:4][OH:5])[CH3:2]
Reactant: CCC(C=O)=CC[C@H]1CCC(C)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(=CC[C@H]1CCC(C)C1(C)C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
2-Ethyl-4-[(1R)-2,2,3-trimethylcyclopentyl]but-2-enal (3a; 8.5 g, 41 mmol) was added dropwise within 10 min. to a stirred suspension of sodium borohydride (1.9 g, 50 mmol) in ethanol (100 ml) at 5-10° C. After additional 2 h stirring at room temperature, the reaction mixture was poured into an ice-cold 0.1 N HCl solution and extracted with MTBE (200 ml). The extract was washed with ice-cold brine (2×100 ml), dried (MgSO4), concentrated in vacuo and the residue was distilled under reduced pressure to give 2-ethyl-4-[(1R)-2,2,3-trimethylcyclopentyl]but-2-en-1-ol (4a) which was further purified by flash chromatography (MTBE/hexane 1:5; 5.8 g, 68% yield, colourless liquid; GC/MS: 2 isomeric pairs of enantiomers 0.5+88.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.N1C=CC=CC=1.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1csc(N)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate (5 g), pyridine (3.36 ml) and dichloromethane (50 ml) was added benzyloxycarbonyl chloride (3.1 ml), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium hydrogen bicarbonate (30 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with diisopropyl ether to give ethyl 2-{[(benzyloxy)carbonyl]amino}-1,3-thiazole-4-carboxylate (5.1 g).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(F)(F)C(=O)O
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCC(F)(F)C(=O)O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (150 mg, 0.483 mmol) and 3-amino-2,2-difluoro-propionic acid (60.4 mg, 0.483 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was then cooled to room temperature and sodium cyanoborohydride (36.4 mg, 0.580 mmol) was added to the stirring solution. The resulting mixture was heated to reflux for 1 h. After cooling to room temperature, citric acid was added, and the solvent removed under vacuum. The resulting solid was suspended in water and collected via filtration. The filtrate was washed thoroughly with water (4×), ether (3×), and hexane (3×). The resulting solid was dried on the filter to give the title compound as a white solid (128.8 mg, 64%). 1H NMR (400 MHz, CDCl3) δ: 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.19 (dd, J=9.0, 2.4 Hz, 1H), 4.45 (s, 2H), 4.40 (m, 1H), 3.61 (t, J=13.8 Hz, 2H), 2.28˜2.31 (m, 2H), 1.92-1.95 (m, 2H), 1.49-1.14 (m, 5H), 0.94 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:26])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH3:18])[CH2:7][O:6]1)=[O:4].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:1][O:2][C:3]([C:5]1([CH3:26])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:23][CH:24]=2)[CH3:18])[CH2:7][O:6]1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccc(O)cc2)CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccc(OS(C)(=O)=O)cc2)CO1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To an ice cold solution of Methyl-5-{4-[1-(4-hydroxy-phenyl)-ethylideneaminooxy]-butyl}-2-methyl-[1,3]dioxane-2-carboxylate (prepared as per example 40) (200 mg) in anhydrous dichloromethane were added triethyl amine (82 mg) and methane sulfonyl chloride (75 mg) and the reaction mixture was stirred at the same temperature for about an hour. Reaction mixture was diluted with dichloromethane, washed with water, dried over sodium sulphate and evaporated under, reduced pressure on a rotavapor. Crude product was flash chromatographed over silica gel using 20% ethyl acetate in petroleum ether as eluent to obtain 200 mg of pure product.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])NC(N)=O>C(O)CCC>[C:1](=[O:6])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC(=O)NC(N)=O
Solvent: CCCCO
Product: CCCCOC(=O)OCCCC
Temperature: 5 °C

Procedure:
The operation was performed for 80 hours in the same apparatuses and procedure as in Example 1 except that butyl allophanate was cooled to 5° C. to deposit in a settling vessel equipped in a lower portion of condenser of distillation column 18 and only butanol was returned to reactor 1 via conduit pipe 22. But, in order to remove butyl allophanate, procedures to withdraw butyl allophanate from the settling vessel every one hour and filter out it from butanol became necessary. The feed rate of urea in a steady state was 73.3 mol/hr, whereas the production rate of dibutyl carbonate to be obtained via reaction liquid withdrawing pipe 14 was 71.1 mol/hr (97.0 mol % to fed urea).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH3:9][N:10]([CH3:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCOCC1>[CH3:9][N:10]([CH3:21])[C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: CN(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)c1ccc(S(=O)(=O)N2CCCC2=O)cc1
Reaction time: 1 h

Procedure:
3.44 g of sodium hydride (at 55-60% in oil) is added to a solution comprising 6.11 g of 2-pyrrolidinone and 200 cm3 of dioxan, with agitation for one hour at ambient temperature. 15.76 cm3 of 4-dimethylaminobenzenesulphonyl chloride [Beritche 43, 3038 (1910)]in solution in 250 cm3 of dioxan is added drop by drop, with agitation for one hour at ambient temperature. The sodium chloride is filtered off on celite, the dioxan is evaporated off under reduced pressure, the residue is crystallized from acetone and 3.90 g of expected product is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CCCCCCC>[Cl:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:34][CH:33]=1
Reactant: COc1nc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)nc4OC)nccc3c2)cc1
Temperature: 80 °C
Yield: 96.8 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ, 97 mg, 0.220 mmol), (6-chloro-2-methoxypyridin-3-yl)boronic acid (45.3 mg, 0.242 mmol), potassium carbonate (91 mg, 0.660 mmol), and pd(ph3p)4 (12.71 mg, 0.011 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (825 μl) and water (275 μl) were added. The vial was sealed and heated to 80° C. for 45 min in a Biotage Initiator microwave reactor. LCMS showed primarily the desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-50% EtOAc/Heptane, then 50-100% EtOAc/Heptane) to give 1-(6-chloro-2-methoxypyridin-3-yl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (117 mg, 0.213 mmol, 97% yield) as a cream-colored foam. m/z (ESI) 548.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.FC(F)(F)C(O)=O.N>>[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(N)cc(O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 74.4 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (36 mg, 0.06 mmol) was treated with trifluoroacetic acid (720 μl, 9.35 mmol) and a solution of ammonia (7N in methanol, 720 μl, 6.04 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 20% dichloromethane-methanol) to obtain 22 mg (75% yield) of the title compound.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](OC)=[O:31])=[C:24]([F:34])[CH:23]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>C1COCC1>[F:34][C:24]1[CH:23]=[C:22]([NH:21][C:19](=[O:20])[O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:27]=[CH:26][C:25]=1/[CH:28]=[CH:29]/[CH2:30][OH:31]
Reactant: COC(=O)/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(/C=C/CO)c(F)c1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A THF solution of diisobutylaluminum hydride (522 mL of a 1.0 M solution, 522 mmol) was added to a cooled (−78° C.) solution of methyl (2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)acrylate (43 g, 130 mmol) in THF (900 mL). After stirring for one hour at −78° C., additional diisobutylaluminum hydride solution was added (140 mL of a 1.0 M solution, 140 mmol). After another 30 minutes, aqueous citric acid and ethyl acetate were added and the mixture allowed to warm slowly to room temperature. The layers were separated and the aqueous phase extracted with more ethyl acetate. Combined organic phases were washed with H2O, brine and dried (MgSO4), filtered and concentrated to give a red oil. The crude product was purified by column chromatography (0-40% ethyl acetate-hexane) to provide the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][CH3:21]>CS(C)=O>[CH3:22][CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][CH2:16][C:4]([CH3:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCC(C)CCCCl
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(CCCC(C)CC)C(=O)OCC
Yield: 95.5 %

Procedure:
First, 4 g (0.1 mol) of NaH as an oil was added to 100 mm of dried DMSO, forming a mixture. Into this mixture, 17.4 g (0.1 mol) of diethyl methylmalonate was dripped, while being stirred on an ice bath. Then, 13.4 g (0.1 mol) of 1-chloro-4-methylhexane was added to the resultant mixture and reacted with it at 70° C. for five hours. thereby obtaining 26 g of crude diethyl 4-methylhexylmethylmalonate (II). This reaction is described as follows: ##STR3##
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[F:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:21])[NH:16]2>ClCCCl>[Br:5][CH2:6][C:7]([C:20]1[C:11]([F:10])=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:21])[CH2:14][CH2:13]2)=[O:8]
Reactant: O=C(Br)CBr
Reactant: O=C1CCc2c(F)cccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C1CCc2c(ccc(C(=O)CBr)c2F)N1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
To a stirring suspension of aluminum chloride (8.0 g, 60 mmol) in 1,2-dichloroethane (16 ml) was added bromoacetyl bromide (4.2 ml, 48 mmol) at 0° C. After 30 min, to a suspension was added 5-Fluoro-3,4-dihydroquinolin-2(1H)-one (4.0 g, 24 mmol) portionwise, then the mixture was allowed to warm to 50° C. and stirred for 4 h. After cooling, the solvent was evaporated in vacuo and the residue was quenched with ice-water and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate=1/1) to afford 6-(Bromoacetyl)-5-fluoro-3,4-dihydroquinolin-2(1H)-one (2.0 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([O:17][CH3:18])([CH3:16])[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.NN>>[F:1][C:2]([F:20])([F:19])[C:3]([O:17][CH3:18])([CH3:16])[CH2:4][NH2:5]
Reactant: COC(C)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Agent: NN
Product: COC(C)(CN)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture comprising 2-(3,3,3-trifluoro-2-methoxy-2-methylpropyl)isoindoline-1,3-dione (272 mg, 0.95 mmol) and hydrazine (0.033 ml, 1.045 mmol) was stirred at 75° C. for 4 hours. After cooling to RT, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title product which was used without further purification (no characterisation data available).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@@H:26]4[CH3:35])=[CH:21][N:20]=3)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=2)=[CH:10][C:9]([F:38])=[CH:8][C:7]=1[N:39]1[CH2:50][CH2:49][N:48]2[C:41](=[CH:42][C:43]3[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=32)[C:40]1=[O:53])(=O)C.[OH-].[Li+]>>[F:38][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:32][O:33][CH2:34]5)[CH2:27][C@@H:26]4[CH3:35])=[CH:21][N:20]=3)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=2)[C:6]([CH2:5][OH:4])=[C:7]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])[CH:8]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 53.3 %

Procedure:
Following the procedures as described for 101, intermediate 103h (80 mg, 0.11 mmol) was hydrolyzed with lithium hydroxide to afford 103 as a yellow solid (40 mg, 53%). LCMS: [M+H]+ 682. 1H NMR (500 MHz, CDCl3) δ 8.56 (dd, J=2.0, 7.0, 1H), 7.95 (t, J=3.0, 1H), 7.82 (d, J=3.0, 1H), 7.47 (t, J=3.0, 1H), 7.31 (dd, J=3.0, 9.0, 1H), 7.17-7.14 (m, 1H), 6.95 (dd, J=2.5, 9.0, 1H), 6.82-6.80 (m, 2H), 4.71-4.61 (m, 4H), 4.56-4.53 (m, 1H), 4.41-4.37 (m, 1H), 4.33-4.28 (m, 1H), 4.23-4.15 (m, 3H), 3.91-3.86 (m, 1H), 3.70 (s, 3H), 3.55-3.44 (m, 2H), 3.08-3.06 (m, 2H), 2.56-2.46 (m, 7H), 2.21-2.16 (m, 1H), 1.27 (s, 6H), 0.98-0.97 (m, 3H)
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][N:7]=1)(=[O:4])=[O:3]>CO.[OH-].[Na+]>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][N:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cn1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cn1
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
A stirred suspension of the product from Step 1 (2.43 g, 8.22 mmol) in MeOH (100 ml) was treated dropwise with 9.2 ml of IN NaOH and kept at 24° C. for 45 minutes. It was then filtered and the filtrate was concentrated to remove methanol. A solution of the residue in water (75 ml) was acidified (PH 2) with IN Hcl (8 ml). The precipitate was collected by filtration, washed with water, dried and recrystallized from MeOH to give 1.19 g of the titled product, mp 217°-219.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:25][CH:26]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:27][N:28]=[N+]=[N-])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH2:7]([O:25][CH:26]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:27][NH2:28])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(CN=[N+]=[N-])OCCCCCCCC/C=C\CCCCCCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CN)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
In 30 ml of tetrahydrofuran was suspended 75 mg (2 mmol) of lithium aluminum hydride. While this suspension was held under ice-cooling, 1.03 g (1.7 mmol) of 2,3-dioleyloxypropyl azide was added dropwise and the mixture was stirred for 30 minutes. Then, the mixture was further stirred at ambient temperature for 2 hours. At completion of the reaction, the reaction mixture was poured in ice-water and extracted with ether and the extract was washed with water, dried, and concentrated. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 0.98 g (98%) of the title compound as colorless oil.