Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].[Cl-].[Na+]>C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At RT and with slight cooling, 99.23 g (394 mmol) of tert-butyl diethylphosphonoacetate were added dropwise to a suspension of 15.74 g (394 mmol) of sodium hydride (60% in mineral oil) in 540 ml of THF. After the addition had ended, the mixture was stirred at RT for 30 min and, after cooling to 0° C., a solution of 60.5 g (358 mmol) of 4-fluoro-3-nitrobenzaldehyde in 324 ml of THF was added. The reaction mixture was stirred at RT overnight and then added to a 10% strength aqueous sodium chloride solution. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (twice) on silica gel (mobile phase petroleum ether/ethyl acetate 9:1). This gave 82.0 g (84.9% of theory) of the target product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[BH4-].[Li+]>O1CCCC1CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)ccc1S(C)(=O)=O
Agent: OCCC1CCCO1
Agent: [BH4-]
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(Cl)cc1CO
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
(Step 2) To a solution of methyl 5-chloro-2-(methylsulfonyl)benzoate obtained in Step 1 (2.65 g) in tetrahydrofuran-ethanol (50 ml+5 ml) was added lithium borohydride (348 mg) at 0° C. The mixture was stirred at 60° C. for 2 hr, treated with ice, and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1) to give [5-chloro-2-(methylsulfonyl)phenyl]methanol (2.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]([O-])=O.[Na+].[O-]S([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.Cl>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:12][NH:1]2)=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1n[nH]c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
2-Amino-4-chloro-benzoic acid (17.16 g, 100 mmol) was suspended in 90 ml of water and 20 ml of concentrated HCl. NaNO2 (6.9 g, 100 mmol) was dissolved in 15 ml water and added slowly at 0° C. The mixture was stirred at 0° C. for 30 minutes and Na2SO3 (34.0 g, 270 mmol) were added, dissolved in 150 ml water. The mixture was then stirred for 2 hours at room temperature. 30 ml of concentrated HCl were added and the mixture stirred overnight at room temperature and then at 80° C. for 2 hours. The solution is treated with aqueous NaOH until the pH is 5.5 and the precipitated was filtered and triturated with ethanol to yield 13.8 g (82%) of 6-chloro-1H-indazol-3-ol. 6-Chloro-1H-indazol-3-ol (700 mg, 4.15 mmol) was dissolved in 25 ml pyridine together with 1-bromo-3-isocyanato-benzene (990 mg, 5 mmol) and stirred at RT for 4 hours. The mixture was then diluted with EtOAc (100 ml) and washed 2× with 1 M HCl. The organic phase was dried with Na2SO4 and reduced under vacuum. The residue was now dissolved in 1 M NaOH and washed with EtOAc and then precipitated with HCl and the precipitate extracted into EtOAc, dried and reduced under vacuum. The product was then recrystallised from EtOAc and heptane to yield 1.1 g (79%) of crystalline solid (m.p. 223-225° C.).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].Br[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na][Na]>C1COCC1.O.[Cl-].[Zn+2].[Cl-]>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH3:2])=[N:7][CH:8]=1
Reactant: CC[Mg]Cl
Reactant: Brc1ccc(Br)nc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Cl-]
Agent: [Na][Na]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A solution of ethylmagnesium chloride (2M in diethyl ether, 21.1 ml, 42.2 mmol) was added to dry THF (75 ml) and then treated with zinc chloride solution (1.0M in diethyl ether, 42.2 ml, 42.2 mmol). The suspension was stirred for 30 minutes at room temperature and was then cooled in ice. Tetrakis-(triphenylphosphine)palladium(0) (0.5 g) was added to the suspension followed by a solution of 2,5-dibromopyridine (5.0 g, 21.1 mmol) in THF (25 ml). The mixture was stirred at 5° C. for 5 hours and then shaken with a suspension of ethylenediamine-tetraacetic acid, disodium salt dihydrate (7.9 g, 21 mmol) in water (100 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The residue was distilled under reduced pressure (60 mm) at an oven temperature of 180° C. using a Kugelrohr (trade mark) apparatus to give the title compound, (2.25 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-]CC.[Na+].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26]Cl)[CH3:23]>C(O)C>[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A solution of 27.8 g (0.2 mol) of 4-nitrophenol in 500 ml of ethanol was treated with 15 g (0.22 mol) of sodium ethoxide. After stirring at room temperature for 30 minutes the solvent was removed under reduced pressure. The residual yellow solid was stirred in a mixture of 160 ml of xylene and 30 ml of water and then treated with 41.4 g (0.3 mol) of potassium carbonate and 34.4 g (0.2 mol) of 2-diethylaminoethyl chloride hydrochloride. The mixture was heated under reflux for 17 hours and filtered while hot. The filter residue was washed with hot xylene and the combined filtrate and washings were evaporated under reduced pressure. Distillation of the residue under a high vacuum gave 31.4 g (66%) of 4-[2-(diethylamino)ethoxy]-nitrobenzene as a liquid.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:13][C:14](=[O:35])[NH:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][CH3:30])=[C:25]([N+:31]([O-])=O)[CH:24]=2)[CH2:17]1)([CH3:12])([CH3:11])[CH3:10].[CH2:36]([N:38]1[C:42]2=[CH:43][N:44]=[CH:45][CH:46]=[C:41]2[CH:40]=[C:39]1[CH:47]=O)[CH3:37]>O.C(O)C.C(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>[C:9]([O:13][C:14](=[O:35])[NH:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([C:23]2[CH:28]=[CH:27][C:26]3[N:29]([CH3:30])[C:47]([C:39]4[N:38]([CH2:36][CH3:37])[C:42]5=[CH:43][N:44]=[CH:45][CH:46]=[C:41]5[CH:40]=4)=[N:31][C:25]=3[CH:24]=2)=[O:34])[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Reactant: CCn1c(C=O)cc2ccncc21
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2ccncc21
Temperature: 100 °C
Yield: 31.7 %

Procedure:
Sodium hydrosulfite (162 mg, 0.793 mmol) dissolved in water (1 mL) was added to a solution of (R)-tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (100 mg, 0.264 mmol) and 1-ethyl-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde (46.0 mg, 0.264 mmol) in ethanol (2 mL) at RT under nitrogen. The reaction mixture was heated to 100° C. in a microwave for 5 h. The reaction mixture was diluted with DCM (20 mL), sodium sulfate was added and the resultant suspension filtered and concentrated in vacuo to yield the crude product. This was purified by Biotage SP4 on a SNAP 10 g silica cartridge using a gradient of 0% (20% MeOH/DCM)/DCM→50% (20% MeOH/DCM)/DCM. Appropriate fractions were combined and evaporated under vacuum to give the title compound (42 mg)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][CH2:12][CH2:11][CH2:10][S:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[S:23])[CH:18]=[CH:19][CH:20]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]([C:22](=[S:23])[NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=3)[CH2:12][CH2:11][CH2:10][S:9]2)=[CH:6][CH:7]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: Brc1ccc(C2NCCCS2)cc1
Product: S=C(Nc1cccc(Cl)c1)N1CCCSC1c1ccc(Br)cc1

Procedure:
The procedure of Example 29 was repeated, except that the reactants consisted of 2.6 g. of 2-(4-bromophenyl)tetrahydro-2H-1,3-thiazine and 1.7 g. of 3-chlorophenyl isothiocyanate. The product was isolated by filtration, washed with benzene, and recrystallized from chloroform/benzene,giving 3.7 g. (86%) of 2-(4-bromophenyl)-N-(3-chlorophenyl)tetrahydro-2H-1,3-thiazine-3-carbothioamide, m.p. 144°-6°. The following elemental microanalysis was obtained:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:53])([CH3:52])[CH2:48][C:49]([NH2:51])=[O:50].NC(C)(C)C(NC(O)C)=O>>[C:49]([CH2:48][C:47]([NH:46][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:45])[CH3:44])=[C:32]([CH3:42])[CH:33]=1)([CH3:53])[CH3:52])(=[O:50])[NH2:51]
Reactant: CC(C)(N)CC(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(O)NC(=O)C(C)(C)N
Product: Cc1cc(OCCCNC(C)(C)CC(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 72 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 3-amino-3-methylbutyramide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-[(2-amino-2-(methyl)propionylamino]ethanol, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:22]([CH3:24])[CH3:23])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(F)cccc23)cc1
Yield: 61.9 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.121 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.088 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][S@](C(C)(C)C)=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.Cl[C:20]([O:22][CH3:23])=[O:21].Cl>C(Cl)Cl>[NH2:12][C@@H:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1)[CH2:2][NH:1][C:20](=[O:21])[O:22][CH3:23]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)NC[C@@H](N)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)—N—((S)-2-amino-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.297 mmol) in DCM (988 μl) was added TEA (124 μl, 0.890 mmol) and methyl chloroformate (24.12 μl, 0.311 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted by EtOAc and the organics were washed with water and brine, dried over sodium sulfate, filtered off, and concentrated in vacuo. The residue was dissolved in Et2O (1 mL), then HCl (4M in dioxane) (148 μl, 0.593 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. After the solvent was decant out, the residue solid was used in next step without further purification. LCMS (m/z): 291.2/293 (MH+), 0.49 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(Oc1ccccc1)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: OCC(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(4-bromophenyl)-2-phenoxyacetic acid (6 g, 19.6 mmol) in anhydrous tetrahydrofuran (100 mL) was added borane-tetrahydrofuran complex (1 M, 40 mL) at −5° C. The solution was stirred at room temperature for 15 hours. After 2 hours, LC-MS showed the desired product was obtained. Water:acetic acid (1:1, 50 mL) was added at 0° C. to quench the reaction, the mixture was added 10 mL saturated sodium bicarbonate to adjust pH=7, extracted with ethyl acetate (100 mL). Then combined and concentrated the organic layers. The crude product was purified by column chromatography (silica gel, dichloromethane/menthol=40:1) to give 2-(4-bromophenyl)-2-phenoxyethanol (5 g, 80%). LCMS (M+H+) m/z: calcd 292.06. found 292.
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>>[OH:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1)=[O:4]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: Cc1ccc(C(O)(C(=O)O)c2ccc(C)cc2)cc1
Product: Cc1ccc(C(O)(C(=O)NCCCN2CCC(c3cc(NC(=O)C(C)C)ccc3C)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 157 was prepared from hydroxy[bis(4-methylphenyl)]acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 8.80–8.59 (s, br, 1 H), 7.91 (s, 1 H), 7.42 (d, 4 H, J=8.4 Hz), 7.15 (s, 1 H), 7.09 (d, 4 H, J=8.0 Hz), 7.04 (d, 1 H, J=8.0 Hz), 6.96–6.78 (br, 1 H), 5.30–5.05 (br, 1 H), 3.55–3.41 (m, 2 H), 3.15–3.00 (m, 2 H), 2.82–2.64 (m, 1 H), 2.59–2.46 (m, 2 H), 2.40–2.27 (m, 1 H), 2.30 (s, 6 H), 2.28 (s, 3 H), 2.17–1.95 (m, 4 H), 1.83–1.56 (m, 4 H), 1.02 (d, 6 H, J=6.8 Hz); ESMS m/e: 556.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[N:26]=[C:25]([C:27]4[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:10]=3[CH:11]([C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[NH:14][C:15]3[S:16][CH:17]=[N:18][N:19]=3)[C:5]2=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:21][C:12]([CH:11]1[C:5]2[C:6](=[N:7][C:2]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:3][CH:4]=2)[O:8][C:9]2[N:26]=[C:25]([C:27]3[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:10]1=2)([CH3:22])[C:13](=[O:20])[NH:14][C:15]1[S:16][CH:17]=[N:18][N:19]=1
Reactant: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(Cl)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1
Reactant: C1CCNC1
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(N4CCCC4)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1

Procedure:
Using conditions described for synthesis of Example 67, the acid from Step 4 of Example 54 was reacted with pyrrolidine and converted Example 70. 1H NMR (400 MHz, chloroform-d) δ ppm 8.90 (1H, s), 8.06 (2H, d, J=8.31 Hz), 7.56 (2H, s), 7.51 (2H, d, J=8.31 Hz), 7.42 (1H, d, J=8.81 Hz), 6.27 (1H, d, J=8.56 Hz), 4.43 (1H, s), 3.53-3.64 (4H, m), 3.19 (3H, s), 3.06 (3H, s), 2.00-2.16 (4H, m), 1.25 (3H, s), 1.23 (3H, s); MS (ES+) m/z: 570 (M+H); LC retention time: 3.88 min (analytical HPLC Method A).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([O:25][CH:26]([F:28])[F:27])=[N:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.O.[H][H]>[Pd].C1COCC1>[F:28][CH:26]([F:27])[O:25][C:13]1[C:12]2[C:16](=[CH:17][C:9]([OH:8])=[CH:10][CH:11]=2)[N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[N:14]=1
Reactant: CC(C)(C)OC(=O)n1nc(OC(F)F)c2ccc(OCc3ccccc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(OC(F)F)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Tert-butyl 6-(benzyloxy)-3-(difluoromethoxy)-indazole-1-carboxylate (262.5 mg) which can be prepared according to the method described in Reference example 33, etc. and 5% palladium on carbon-STD-type-50% wet with water (109.9 mg; manufactured by N. E. Chemcat Corp.) were suspended in dehydrated THF (3.4 mL; manufactured by Kanto Chemical Co., Inc.). After replacing the reaction system with hydrogen, it was stirred overnight at room temperature. After replacing the reaction solution with nitrogen, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (197.2 mg).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([O:12][C:13](=[O:20])[C@H:14]([C@H:16]([CH2:18][CH3:19])[CH3:17])[NH2:15])[CH:10]=[CH2:11].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH2:9]([O:12][C:13](=[O:20])[C@H:14]([C@H:16]([CH2:18][CH3:19])[CH3:17])[NH2:15])[CH:10]=[CH2:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C=CCOC(=O)[C@@H](N)[C@@H](C)CC
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of isoleucine allyl ester, prepared as described by H. Waldmann and H. Kunz in Liebigs Ann. Chem., 1983, 1712-1725, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give isoleucine allyl ester isocyanate.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]>CN(C)C=O.C([O-])(O)=O.[Na+]>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][C@H:13]([CH3:17])[C:14]([O:16][CH2:10][CH2:11][CH2:4][CH2:5][CH2:6][CH3:7])=[O:15])=[CH:5][CH:6]=1)=[O:9]
Reactant: CC(Cl)C(=O)O
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)[C@@H](C)Oc1ccc(C=O)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Sodium hydride (0.4 mole) was suspended in dimethyl formamide (20 ml). 4-Hydroxybenzaldehyde (0.2 mole) in DMF (50 ml) was added. After the effervesence had subsided, 2-chloropropanoic acid (0.22 mole) was added dropwise. During the addition the reaction temperature rose to 70° C. The mixture was stirred overnight at 110° C. Upon cooling the mixture was diluted with saturated NaHCO3 solution and extracted with ethyl acetate (3×100 ml). The aqueous phase was then acidified with concentrated HCl solution and extracted with ethyl acetate. After washing the second organic extract with water and evaporation, a brown oil was obtained. Crystallisation from hot chloroform and hexane gave a brown solid (7.6 g). The mother liquors were evaporated to dryness to yield a brown solid (17.3 g) used without further purification. (Total yield 64%). 'H-NMR spectroscopy showed these products to be greater than 90% pure (m.p. 114°-8° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([NH2:9])=[O:8])([O-])=O.[H][H]>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1
Reactant: [H][H]
Solvent: O
Product: NC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
To a suspension of 3-nitro-4-phenoxy-5-sulphamyl-benzamide (2.4 g) in water (25 ml) 1N lithium hydroxide (10 ml) was added. The resulting solution was hydrogenated at room temperature and at 1.1 atmospheres hydrogen pressure after addition of Pd-on-carbon catalyst (0.2 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was then adjusted to pH 7.5 by addition of 4N hydrochloric acid. The precipitated 3-amino-4-phenoxy-5-sulphamyl-benzamide was isolated and dried in vacuo. The compound was obtained with a melting point of 291°-292° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:16]=[CH:15][C:9]([CH2:10][N:11]3[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[N:11]1([CH2:10][C:9]2[CH:15]=[CH:16][C:6]([O:5][CH:3]3[CH2:2][N:1]([C:30]([C:28]4[O:29][C:25]([C:22]5[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)=[N:26][N:27]=4)=[O:31])[CH2:4]3)=[CH:7][CH:8]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: c1cc(OC2CNC2)ccc1CN1CCC1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC5)cc4)C3)o2)cc1
Yield: 67.2 %

Procedure:
Using a similar protocol as described in Example 36 employing 41A (0.10 g, 0.46 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.13 g, 0.52 mmol) as starting materials afforded 130 mg (68%) of 41 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.08 (m, 2H), 3.19 (t, 4H), 3.51 (s, 2H), 3.89 (s, 3H), 4.32 (d, 1H), 4.64 (dd, 1H), 4.74 (d, 1H), 5.06 (m, 1H), 5.11 (m, 1H), 6.72 (d, 2H), 7.02 (d, 2H), 7.21 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 421 [M+H]+, LC purity: 95%.