Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27](=[O:41])[NH:28]/[C:29](=C(/OCC)\CCC)/[C:30]([NH:32][NH2:33])=O)([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]3[C:6]([CH2:8][CH2:13][CH3:12])=[N:33][N:32]=[C:30]3[CH2:29][NH:28][C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:41])=[CH:18][CH:19]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: CCC/C(OCC)=C(\NC(=O)OC(C)(C)C)C(=O)NN
Solvent: CCO
Product: CCCc1nnc(CNC(=O)OC(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Yield: 30366.2 %

Procedure:
4′-Aminomethylbiphenyl-2-carboxylic acid t-butyl ester (1.5 g, 5.2 mmol) and [1-ethoxy-but-(E)-ylidene-hydrazinocarbonylmethyl] carbamic acid t-butyl ester (1.0 g, 3.5 mmol) were combined and dissolved in ethanol (50 mL). The mixture was heated at 50° C. for 2 hours and then 70° C. overnight. The mixture was then cooled and concentrated. The product was purified by silica gel chromatography (0-20% MeOH:DCM) to obtain intermediate (23a) (400 g). MS m/z: [M+H+] calcd for C29H38N4O4, 507.6; found 507.3.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.C(OCC)C.O>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:1])([NH:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:10])[CH3:7])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CCCO)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCC(C)(C)NC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-methyl-4-(p-nitrobenzyloxycarbonyl)aminopentanol (1.63 g) and p-toluenesulfonyl chloride (2.3 g) in pyridine (17 ml) was allowed to stand at 5° C. overnight. The reaction mixture was diluted with diethyl ether and water, washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to give 5-p-toluenesulfonyloxy-2-methyl-2-(p-nitrobenzyloxycarbonyl)aminopentane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])=[N+]=[N-].N#N.CO>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[CH2:23][NH2:20]
Reactant: [N-]=[N+]=NCc1ccc(F)cc1Cl
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Add triphenylphosphine (129.9 g, 495 mmol) to a solution of 1-azidomethyl-2-chloro-4-fluoro-benzene (61.2 g, 330 mmol) in THF (500 mL) and water (30 mL). Stir at RT until no more N2 is evolved. Add 100 mL MeOH and stir at RT overnight. Concentrate; acidify to pH 1 with 1N HCl solution, wash with CH2Cl2 (3 times). Basify aqueous layer with 5N NaOH solution, extract with CH2Cl2 (3 times), dry over MgSO4. Concentrate to afford the title compound (38.5 g, 73%) as a clear liquid. MS(IS) 160 (M+1). 1H NMR (400 MHz, CDCl3): 3.90 (s, 2H); 6.96 (t, 1H, J=6.4 Hz); 7.11 (d, 1H, J=8.3 Hz); 7.36 (t, 1H, J=6.4 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH2:24][CH2:25][CH2:26][CH3:27])=[O:10])=[CH:7][CH:6]=1.[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2([C:11]3[C:15]4[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=4[O:13][C:12]=3[CH2:24][CH2:25][CH2:26][CH3:27])[O:32][CH2:31][CH2:30][O:10]2)=[CH:28][CH:29]=1
Reactant: CCCCc1oc2ccc(C(=O)OC)cc2c1C(=O)c1ccc(OCCBr)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCc1oc2ccc(C(=O)OC)cc2c1C1(c2ccc(OCCBr)cc2)OCCO1
Yield: 45.1 %

Procedure:
10.0 g (0.022 mol) of methyl 3-[4-(2-bromoethoxy)benzoyl]-2-butylbenzofuran-5-carboxylate, 3.39 g (0.055 mol) of ethylene glycol, 890 mg of para-toluenesulfonic acid (pTsA) and 100 ml of benzene are brought to reflux for 3 days, eliminating the water formed using a Dean-Stark apparatus. The mixture is evaporated to dryness and the residue is chromatographed on a column of silica, eluting with DCM (dichloromethane) and then a DCM/ethyl acetate (99/1) mixture. 5 g of the pure desired compound are thus isolated.
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[C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([C@@H:36]3[C@@H:39]([CH2:40][CH2:41][C@@H:42]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[OH:43])[C:38](=[O:51])[N:37]3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)(=O)C.C(N(CC)CC)C.O>CO>[F:50][C:47]1[CH:48]=[CH:49][C:44]([C@@H:42]([OH:43])[CH2:41][CH2:40][C@H:39]2[C:38](=[O:51])[N:37]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C@@H:36]2[C:33]2[CH:32]=[CH:31][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([C@@H:6]4[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]4[OH:4])[CH:25]=3)=[CH:35][CH:34]=2)=[CH:45][CH:46]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccccc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c3)cc2)N1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol (10.5 mg, 0.013 mmol) was dissolved in 0.30 mL of methanol and 0.30 mL of triethylamine followed by drop-wise addition of water (0.80 mL). The yellowish mixture stirred at room temperature overnight. LCMS of the solution confirmed complete consumption of the starting material and formation of the fully deprotected material. The mixture was concentrated in vacuo, and purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford 2.8 mg (35%) of the desired (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a white powder; 1H NMR (300 MHz, CD3OD) δ 7.65 (d, J=11.1 Hz, 2H), 7.54-7.23 (m, 10H), 7.05-6.89 (m, 3H), 4.61 (t, J=6.3 Hz, 1H), 4.19 (d, J=9.0 Hz, 1H), 3.87 (d, J=10.7 Hz, 1H), 3.73-3.63 (m, 1H), 3.49-3.36 (m, 3H) 3.22-3.18 (m, 2H), 1.89 (m, 4H) ppm; MS [M−OH]+ 596.5.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH:2]=[CH2:3].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[CH2:22]([O:25][C:26]1([CH3:55])[CH2:31][CH2:30][N:29]([C:32]2[N:37]3[N:38]=[C:39]([CH2:41][NH2:42])[CH:40]=[C:36]3[N:35]=[C:34]([CH3:43])[C:33]=2[C@H:44]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:28][CH2:27]1)[CH:23]=[CH2:24].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:42][CH2:41][C:39]1[CH:40]=[C:36]2[N:35]=[C:34]([CH3:43])[C:33]([C@H:44]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:32]([N:29]3[CH2:30][CH2:31][C:26]([O:25][CH2:22][CH:23]=[CH2:24])([CH3:55])[CH2:27][CH2:28]3)[N:37]2[N:38]=1)=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1C(=O)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN)nn23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CNC(=O)c4ccccc4CC=C)nn23)CC1
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.10 g, 0.200 mmol) and Ph3P (0.063 g, 0.240 mmol) in 9:1 THF/H2O (5 mL) stirred at rt for 1 h and at 45° C. for 4 h. Then, diluted with Et2O (25 mL) and extracted with 0.5M HCl (2×5 mL). The combine aqueous layers neutralized with sat Na2CO3 and extracted with CH2Cl2 (2×20 mL). The combine CH2Cl2 layers dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as viscous pale yellow oil which was used in the subsequent step without purification. To a stirred solution of 2-allylbenzoic acid (0.065 g, 0.400 mmol) in CH2Cl2 (5 mL) containing cat. DMF was added 2M oxalyl chloride/DCM (0.400 ml, 0.801 mmol) at rt. After 1 h, concentrated and the resulting residue was re-dissolved in CH2Cl2 (3 mL) and added to a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and DIEA (0.105 ml, 0.600 mmol) in CH2Cl2 (2 mL) at rt. After 2 h the reaction was quenched with a drop of MeOH, concentrated and purified prep-HPLC to afford (S)-ethyl 2-(2-((2-allylbenzamido)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.059 g, 0.096 mmol, 47.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (dd, J=1.2, 7.7 Hz, 1H), 7.37-7.41 (m, 1H), 7.24-7.30 (m, 3H), 6.46-6.53 (m, 1H), 6.49 (s, 1H), 5.98-6.06 (m, 1H), 5.83-5.98 (m, 2H), 5.39 (dd, J=1.6, 17.2 Hz, 1H), 5.14 (d, J=9.8 Hz, 1H), 5.06 (qd, J=1.5, 10.1 Hz, 1H), 5.01 (qd, J=1.7, 17.2 Hz, 1H), 4.84 (d, J=5.4 Hz, 2H), 4.15-4.28 (m, 2H), 3.97 (d, J=4.6 Hz, 2H), 3.64 (d, J=6.3 Hz, 2H), 2.61 (s, 3H), 1.98 (d, J=13.2 Hz, 1H), 1.84-1.94 (m, 2H), 1.70 (d, J=9.3 Hz, 1H), 1.31 (s, 3H), 1.21-1.26 (m, 12H). LCMS (M+H)=618.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20]C)=[CH:11][N:12]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])=[CH:11][N:12]=1
Reactant: COC(=O)CCCCc1ncc(-c2cc(Cl)ccc2OC)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCCCc1ncc(-c2cc(Cl)ccc2O)o1
Temperature: -78 °C
Reaction time: 27 h
Yield: 81.7 %

Procedure:
Dissolve 5-[5-(5-chloro-2-methoxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (4.174 g, 12.89 mmol) in 50 mL of CH2Cl2 and cool the solution to −78° C. Add boron tribromide (48.9 mL of a 1M solution in CH2Cl2) dropwise to the reaction and allow it to warm to ambient temperature and allow it to stir for 27 hours. Cool the reaction to −78° C. and quench it by adding 100 mL of MeOH dropwise to the reaction mixture. Allow the reaction to warm to ambient temperature and stir for 19 hours. Concentrate the reaction mixture in vacuo. Dissolve the residue in CH2Cl2 and wash it with saturated aqueous NaHCO3 and brine. Dry the organic layer with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Purify the residue using silica gel chromatography eluting with hexanes/ethyl acetate mixtures to afford 3.26 g of the titled product (82%): mass spectrum: m/z=310.09 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](/[CH:13]=C/C3C=CC=CC=3)=[N:10][O:11][CH:12]=2)=[CH:4][CH:3]=1.[O:21]=[O+][O-].CSC>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:13]=[O:21])=[N:10][O:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2conc2/C=C/c2ccccc2)cc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: O=Cc1nocc1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 15 h

Procedure:
(E)-4-(4-Chlorophenyl)-3-styrylisoxazole (2 g, 7.1 mmol) was dissolved in DCM/MeOH (20 mL/2 mL) and cooled to −78° C. The reaction was placed under ozonolysis conditions (O3 bubbling) until full disappearance of starting material. DMS (8 mL) was added and the reaction was let warm to ambient temperature. After 15 h, the reaction was partitioned between EtOAc and H2O. The organics were separated, washed with saturated aqueous NaHCO3, and dried with saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product: MS (m/z) 208.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=[O:31].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30]([OH:32])=[O:31])[CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4cccc(C(=O)O)c4)CC3)nc2)c1

Procedure:
3-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 3-bromo benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C27H30N4O3 (m/e) 458, obsd 459 (M+H).
Reaction SMILES: [CH2:1]=[C:2]([CH:6]([O:11][C:12](=[O:14])[CH3:13])[C:7]([Cl:10])([Cl:9])[Cl:8])[C:3]([O-:5])=[O:4].[CH2:15]=[C:16]([CH:20](O)[C:21](Cl)(Cl)Cl)C([O-])=O.[BH4-].[Na+].CC(=CC(Cl)(Cl)Cl)C(OCCCC)=O>O1CCCC1>[CH3:1][CH:2]([CH:6]([O:11][C:12](=[O:14])[CH3:13])[C:7]([Cl:9])([Cl:10])[Cl:8])[C:3]([O:5][CH2:15][CH2:16][CH2:20][CH3:21])=[O:4]
Reactant: C=C(C(=O)[O-])C(O)C(Cl)(Cl)Cl
Reactant: C=C(C(=O)[O-])C(OC(C)=O)C(Cl)(Cl)Cl
Agent: CCCCOC(=O)C(C)=CC(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C(C)C(OC(C)=O)C(Cl)(Cl)Cl
Temperature: 70 °C

Procedure:
1236.1 g of crude 2-methylene-3-acetoxy-4,4,4-trichlorobutyrate (91.3%) containing about 2.5% 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate and 747 ml of tetrahydrofuran was charged to a 2-liter flask equipped with a reflux condenser, magnetic stir bar, and a thermometer. 38.0 g of sodium borohydride was added in three portions to the stirred solution. The reaction temperature rose to 32° C. The reaction was heated slowly to 70° C. for three hours. NMR indicated 80% of the starting material was converted into product, butyl 2-methyl-4,4,4-trichlorobut-2-enoate. The reaction was heated for another six hours at 80° C. and the reaction was quenched by removal of tetrahydrofuran and addition of water. The organic layer was separated and GC analysis showed the presence of 79.2% butyl 2-methyl-4,4,4-trichlorobut-2-enoate, 1% butyl 2-methyl-2,4,4-trichlorobut-3-enoate, 6.6% unreacted starting material, butyl 2-methylene-3-acetoxy-4,4,4-trichlorobutyrate, 3% butyl 2-methyl-3-acetoxy-4,4,4-trichlorobutyrate, and 0.5% butyl 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate. Hydrogenated product, butyl 2-methyl-3-acetoxy-4,4,4-trichlorobutyrate, was formed owing to the presence of water or traces of other protonic solvents in the reaction system.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:20]3[CH2:22][CH2:21]3)=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.Cl.[CH:35]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:20]3[CH2:22][CH2:21]3)=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:41][S:38]([CH:35]1[CH2:37][CH2:36]1)(=[O:40])=[O:39])=[O:9]
Reactant: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Reaction time: 0.33 h
Yield: 21.9 %

Procedure:
5-chloro-4-(5-chloro-6-cyclopropylpyridin-3-yloxy)-2-fluorobenzoic acid (Preparation 265, 15 mg, 0.44 mmol), 4-dimethylaminopyridine (81 mg, 0.66 mmol), and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (127 mg, 0.66 mmol) were suspended in dichloromethane (2.5 mL). The reaction mixture was stirred for 20 minutes then dimethyl formamide (4 mL) was added and the suspension was stirred for 10 minutes. Cyclopropanesulfonamide (107 mg, 0.88 mmol) and N,N-diisopropylethylamine (160 μL, 0.88 mmol) were added and the reaction mixture was stirred for 18 hours at room temperature. The crude reaction mixture was purified by semi-preparative reverse phase HPLC (Column phenomenex Luna C18 150×21.2 mm 110 A 5μ, 3 injections of 2 ml, detection at 254 nm, fractions of 5 ml each, Gradient Solvent A: 0.05% HCO2H in acetonitrile, Solvent B: 0.05% HCO2H in water; 0 min 10% A, 2.5 min 10% A, 32.5 min 95% A, 37.5 min 95% A then return to initial conditions, flow rate 15 ml/min) to afford the title compound as a white solid (43 mg, 22%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]O)=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1.N1C=CC=CC=1.C(Cl)[Cl:25]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][Cl:25])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCO
Reactant: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)ccc1CCCl
Temperature: 0 °C
Yield: 98 %

Procedure:
12 g thionyl chloride (7.4 ml, 100 mmol) in 10 ml toluene (abs.) are quickly added in a drop-wise manner to a solution of 6.78 g 2-(4-chloro-2-nitrophenyl)ethanol (33 mmol) in 100 ml abs. toluene and 2.5 ml pyridine. This is heated 2 h under reflux, cooled, poured onto 100 g ice and mixed with 100 ml CH2Cl2. The aqueous phase is extracted 2× each with 50 ml CH2Cl2. The combined organic phases are neutralized 2× each with 80 ml saturated bicarbonate solution, dried over Na2SO4, filtered and rotary evaporated. 7.12 g (32 mmol, 98%) 2-(4-chloro-2-nitrophenyl)ethyl chloride are obtained as a brown oil which hardens to a brown solid after some days in the refrigerator.
Reaction SMILES: C([O:4][CH:5]1[CH2:14][CH:13]2[CH2:15][CH:6]1[CH:7]1[CH:12]2[CH:11]2[CH2:16][CH:8]1[CH:9]=[CH:10]2)(=O)C.O1CCOCC1.[OH-].[K+].O.O.C(O)(=O)C(O)=O>O>[OH:4][CH:5]1[CH2:14][CH:13]2[CH2:15][CH:6]1[CH:7]1[CH:12]2[CH:11]2[CH2:16][CH:8]1[CH:9]=[CH:10]2
Reactant: CC(=O)OC1CC2CC1C1C3C=CC(C3)C21
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: OC1CC2CC1C1C3C=CC(C3)C21
Reaction time: 4 h
Yield: 95 %

Procedure:
100 parts of 8-acetoxytetracyclo[4.4.0.12,5.17,10]dodec-3-ene, 200 parts of 1,4-dioxane, 50 parts of distilled water, and 50 parts of potassium hydroxide were placed in a flask. A hydrolysis reaction was carried out for 4 hours in a nitrogen atmosphere at 100° C. After cooling, an aqueous solution of oxalic acid di-hydrate in an amount of 1.1 equivalent of the potassium hydroxide was added dropwise to coagulate the reaction product. The coagulate was washed with a large amount of water, then washed with a small amount of toluene, and dried to obtain 8-hydroxytetracyclo [4.4.0.12,5.17,10]dodec-3-ene of the following formula (14) at an yield of 95%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCCCCNC1CCCCC1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound (28.8 mg) obtained in Example 3-2 was dissolved in methanol (0.5 ml). The solution was added with cyclohexanone (8.80 μl) and sodium cyanoborohydride (4.40 mg) and then adjusted to approximately pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by the addition of 1 mol/l hydrochloric acid to extract the objective substance. Subsequently, the aqueous layer was concentrated under reduced pressure and then the residue was purified through a solid-phase extraction column (Bond Elut® C18 (manufactured by Varian Inc.), 200 mg), thereby obtaining hydrochloride (17.6 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([OH:6])[CH3:5])[CH2:3][CH2:2]1.[C:7](Cl)(Cl)=[O:8].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1>CCOCC>[CH:1]1([CH:4]([O:6][C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:14][CH:13]=2)=[O:8])[CH3:5])[CH2:3][CH2:2]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)Cl
Reactant: CC(O)C1CC1
Solvent: CCOCC
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)OC(C)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.8 %

Procedure:
4.3 g (49.9 millimoles) of 1-cyclopropylethanol are added dropwise to a stirred solution of 9.9 g (100 millimoles) of phosgene in 100 ml of absolute ether at 0° C. The reaction solution is then stirred for 1 hour at 0° C. followed by one hour at room temperature, and the excess phosgene is removed by means of a dry stream of nitrogen, after which the ether is removed under reduced pressure at room temperature. The 1-cyclopropylethyl chloroformate which is left (6.6 g) is reacted with 5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone by the method described in Example 31. The reaction mixture is also worked up as described in Example 31. After recrystallizing the product first from dimethylformamide/water and then from ethanol/ether, 1.3 g (17% of theory) of 6-[p-(1-cyclopropylethoxycarbonylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals of melting point 223°-224° C.