Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:23])(=[O:3])[CH3:2].CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:10][C:9]1=[O:23])(=[O:3])[CH3:2]
Reactant: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCC[C@@H](/C=C/[C@H]1C(=O)C=C[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O

Procedure:
to a solution of 26 parts of methyl (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oate in 200 parts of acetone at -10° is added 100 parts of Jones reagent. The resultant mixture is stirred at -10° for 7 minutes, then diluted with 10 volumes of water. The mixture thus obtained is extracted with dichloromethane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The oily residue is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvent. From an eluate comprising 5% ethyl acetate in benzene, on evaporation of solvent, methyl (5Z,13E,15S)-15-acetyloxy-11-oxoprosta-5,9,13-trien-1-oate is obtained as a pale yellow oil. The product has the formula ##SPC3##
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH4+].[C:11]([NH:14]C1C=NC=C(C=1)C([O-])=O)(=[O:13])[CH3:12]>>[C:11]([NH:14][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[C:1]([NH2:9])=[O:8])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1cncc(C(=O)[O-])c1
Reactant: NC(=O)c1cccnc1
Agent: [NH4+]
Product: CC(=O)Nc1cncc(C(N)=O)c1

Procedure:
The above salt is converted to the desired nicotinamide derivative by conversion to the methyl ester and then to the corresponding amide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1.CO.[ClH:17]>O1CCCC1.CCOCC>[ClH:17].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1cc2cc(C#N)ccc2c(N)n1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2cc(CN)ccc2c(N)n1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-amino-6-cyano-3-methylisoquinoline (0.68 g) in 15 mL of tetrahydrofuran at room temperature under a nitrogen atmosphere was added 8.4 mL of 2M borane-methylsulfide complex in tetrahydrofuran and thereafter heated at 60° C. for 50 minutes. The reaction mixture was cooled in an ice bath and 7.5 mL of methanol was added slowly. After 15 minutes 18.8 mL of 1M hydrogen chloride in ether was added. The reaction mixture was allowed to warm to room temperature and stirred for an additional 16 hours. The solid was isolated to afford 0.34 g of 1-amino-6-(aminomethyl)-3-methylisoquinoline hydrogenchloride. The filtrate was purified using column chromatography (silica gel; methanol/ammonia=98/2) to yield an additional 0.15 g of 1-amino-6-(aminomethyl)-3-methylisoquinoline. ESI-MS: 188 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH:28]=[N:27][NH:26][C:25]=3[CH2:24]2)[C:11](=O)[N:10]1[CH3:32].C(N(CC)CC)C.[CH:40]1([S:43](Cl)(=[O:45])=[O:44])[CH2:42][CH2:41]1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48].C(Cl)Cl>ClCCl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:43]([CH:40]4[CH2:42][CH2:41]4)(=[O:45])=[O:44])[CH:28]=3)[CH2:24]2)[CH2:11][N:10]1[CH3:32]
Reactant: CN1C(=O)[C@H](N2Cc3cn[nH]c3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of tert-butyl [(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-1-methyl-6-oxopiperidin-3-yl]carbamate (70 mg, 0.161 mmol) in dichloromethane (4 mL) at room temperature, triethylamine (0.068 mL, 0.484 mmol) and cyclopropanesulfonyl chloride (0.037 mL, 0.363 mmol) were added. The mixture was stirred for 4 days at room temperature. The residue was purified by preparative TLC on silica gel, eluting with CH2Cl2/MeOH/aqueous NH3 (95/4/1) to give first eluting isomer as isomer A and second eluting isomer as isomer B. Isomer A was treated with TFA/CH2Cl2=1:1 for 1 h to give the title compound. LC-MS: 437.89 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[N:6][C:7]=1[CH3:8].[CH:16](OCC)=[O:17].[H-].[Na+]>C(COC)OC>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([CH:16]=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1cnc(C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cnc(C)c(C)c1

Procedure:
Reaction of ethyl 3-(5,6-dimethyl-3-pyridyl)propionate with ethyl formate and sodium hydride in dimethoxyethane at room temperature gave ethyl 3-(5,6-dimethyl-3-pyridyl)-2-formylpropionate, m.p. 148°-9°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=O)[CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[S:62]1[C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=2[N:64]=[C:63]1[NH2:71]>ClCCl.C(OCC)(=O)C>[S:62]1[C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=2[N:64]=[C:63]1[NH:71][C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]([CH3:21])[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:17][CH2:16]2)=[O:20]
Reactant: Nc1nc2ccccc2s1
Reactant: CC1c2c(cccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1c2c(cccc2C(=O)Nc2nc3ccccc3s2)CCN1C(=O)OC(C)(C)C

Procedure:
A mixture of EXAMPLE 43A (400 mg), PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 714 mg), triethylamine (0.383 mL) and benzo[d]thiazol-2-amine (247 mg) in dichloromethane (10 mL) was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL), washed with brine (30 mL×3), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (silica gel, petroleum ether/ethyl acetate=1/1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].[CH:15]([N:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][CH:21]3[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]3)=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)N1CCC(O)CC1
Reactant: COC(=O)c1cc2cc(O)ccc2s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2s1
Reaction time: 2 h

Procedure:
The above prepared 5-hydroxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.143 g, 0.687 mmol) was dissolved in 3.4 mL of THF and treated successively at 10° C. with 1-isopropyl-piperidin-4-ol (0.197 g, 2 eq.), triphenylphosphine (0.360 g, 2 eq.) and DIAD (0.267 mL, 2 eq.), and the mixture then kept at ambient temperature for another 2 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=5/95), delivered 0.222 g of the title compound as light yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:15][C:16]1[C:50]([CH:51]=[O:52])=[CH:49][CH:48]=[CH:47][C:17]=1[C:18]([O:20][C@H:21]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)[CH2:22][C:23]1[C:28]([Cl:29])=[CH:27][N+:26]([O-:30])=[CH:25][C:24]=1[Cl:31])=[O:19])C1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:51]([C:50]1[C:16]([OH:15])=[C:17]([CH:47]=[CH:48][CH:49]=1)[C:18]([O:20][C@H:21]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:40])[F:41])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)[CH2:22][C:23]1[C:24]([Cl:31])=[CH:25][N+:26]([O-:30])=[CH:27][C:28]=1[Cl:29])=[O:19])=[O:52]
Reactant: O=Cc1cccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1cccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
TFA (0.4 mL) was carefully added to a solution of [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-benzyloxy-3-formyl-benzoate (116 mg, 0.18 mmol) in toluene (0.8 mL) at 0° C. The resulting mixture was stirred at 0° C. for 50 minutes. The solution was diluted with DCM (20 mL) and sat. NaHCO3 (20 mL). The layers were separated over a hydrophobit fit and the organic phase concentrated in vacuo, the residue azeotroped with toluene to dryness. The yellow gum (120 mg) was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[CH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Reactant: COC(=O)CCC=O
Product: COC(=O)CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
The title compound was prepared from 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Ex. 4.1 step 1) and methyl 4-oxobutanoate analogously to Example 10, step 1;
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([Si:15]([CH3:36])([CH3:35])[O:16][CH:17]1[CH2:22][CH:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C:19]([OH:34])([C:31]([O-])=[O:32])[CH2:18]1)([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH:21]1[CH2:22][CH:17]([O:16][Si:15]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:35])[CH3:36])[CH2:18][C:19]([OH:34])([CH2:31][OH:32])[CH2:20]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(O[Si](C)(C)C(C)(C)C)CC(O)(C(=O)[O-])C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CC(O[Si](C)(C)C(C)(C)C)CC(O)(CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
Diisobutyl aluminum hydride (6 mL, 9 mmol, 1.5M in toluene) was added to a solution of the ester 14 (0.56 g, 1.3 mmol) in anhydrous toluene (20 mL) at -78° C. After 20 min the solution was warmed to 0° C. and stirred for 1 h. The solution was slowly quenched by adding to a stirred 0° C. solution of 2N potassium sodium tartrate. Ethyl acetate was added and the organic layer separated and the water phase extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The material was further purified by column chromatography on silica gel with ethyl acetate hexane mixtures to give the diol 15 (0.3 g, 59%) 1H NMR (CDCl3, 500 MHz) δ 0.11 (s, 3H), 0.12 (s, 3H), 0.14 (s, 3H), 0.16 (s, 3H), 0.90 (s, 9H), 0.91 (s, 9H), 1.28 (dd, 1H), 1.43 (dd, 1H), 2.00 (ddd 3H), 2.16 (dd, 1H), 3.33 (dd, 1H), 3.40 (dd, 1H), 4.34 (m, 2×1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH:17][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1)c1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
4-[(E)-2-(4-Nitrophenyl)ethenyl]-1,3-thiazol-2-amine (300 mg) and N,N-dimethylaniline (4 ml) were combined under nitrogen atmosphere, and then benzoyl chloride (0.31 ml) was added dropwise to the suspension. The reaction mixture was stirred at 110° C. for 2 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate. The organic solution was washed with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with ethyl ether to give N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}benzamide (298.6 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:6](=[C:12](OC)[CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(OCC)=[O:2].C(O)(=O)C.[CH:21]([NH2:23])=[NH:22].[OH-].[K+].C(O)(=O)C>C(O)C>[CH2:13]([C:12]1[N:23]=[CH:21][N:22]=[C:1]([OH:2])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:14]
Reactant: CCOC(=O)C(C(=O)OCC)=C(CC)OC
Reactant: N=CN
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(O)ncnc1CC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 2-carboethoxy-3-methoxy-2-pentenoate (11.00 g, 47.77 mmol) in ethanol (40 ml) was stirred under ice-cooling. To the mixture was added a formamidine acetic acid salt (5.96 g, 57.25 mmol), followed by addition of an aqueous solution of potassium hydroxide (85% potassium hydroxide 6.94 g (105.13 mmol)/water 40 ml). Then, the mixture was stirred at room temperature for 16 hours and the pH was adjusted to 7 by adding acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][C:11]2[C:3]=1[N:4]=[C:5]1[C:10]=2[CH:9]=[CH:8][C:7]([F:19])=[CH:6]1.O(C)S([C:24](F)(F)F)(=O)=O>C1(C)C=CC=CC=1.C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH+:12]([CH3:24])[C:11]2[C:3]=1[N:4]=[C:5]1[C:10]=2[CH:9]=[CH:8][C:7]([F:19])=[CH:6]1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Fc1ccc2c3[nH]c4ccccc4c(Cl)c-3nc2c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[NH+]1C2=c3ccc(F)cc3=NC2=C(Cl)c2ccccc21
Product: Cl
Reaction time: 24 h
Yield: 159.6 %

Procedure:
To a solution of 11-chloro-8-fluoroquindoline from Example 89 (1.00 g, 3.69 mmol) in toluene (25 ml, freshly distilled) stirring under nitrogen was added methyl triflate (1.05 mL, 9.24 mmol). The mixture stirred for 24 h at room temperature and was diluted with diethyl ether (60 mL) and filtered. The orange filter cake was placed under high vacuum for 24 h. The orange residue was suspended in chloroform and adsorbed onto neutral alumina and chromatographed over basic alumina (eluting with chloroform-ethyl acetate gradient from 1:0 to 1:1 until the eluent was free of impurities by TLC then eluting with 3% methanol in chloroform). The violet fractions were collected and concentrated to a small volume (50 mL). The violet solution was acidified with ethereal 1M HCl to a bright yellow endpoint. The mixture was cooled below room temperature and filtered. The filter cake rinsed with diethyl ether (10 mL) and dried under high vacuum at 45° C. for several days to yield 0.949 g (90%) of the title compound as a bright orange solid. A portion of this material was further purified by HPLC. The title compound is poorly soluble in all common NMR solvents; 1H NMR (DMSO-d6) δ 13.55 (s, 1H), 8.93 (dd, J=9.0, J=5.2, 1H), 8.87 (d, J=8.8, 1H), 8.68 (d, J=8.0, 1H), 8.27 (t, J=8.0, 1H), 8.11 (t, J=7.6, 1H), 7.64 (dd, J=9.0, J=2.2, 1H), 7.47 (J=9.2, J =2.2, 1H), 5.00 (s, 3H); MS (FAB, m/z) 285 (M+).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.[OH:17][CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1.[H-].[Na+]>O1CCOCC1>[O:20]1[CH2:21][CH2:22][CH:18]([O:17][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1
Reactant: OC1CCOC1
Reactant: ClCc1ccccc1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(COC2CCOC2)cc1

Procedure:
Thus, benzylchloride or benzylbromide can be reacted at elevated temperature with the alkololate from 3-hydroxytetrahydrofurane and sodium hydride, suspended in dioxane to yield the (3-tetrahydrofuryl)-benzylether which is an active herbicide against grassy weeds (German Offenlegungsschrift No. 2724675).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[CH2:42][CH3:43])=[CH:32][CH:33]=3)[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-:44].[Ca+2].[Cl-]>C(O)(C(F)(F)F)=O>[ClH:44].[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[CH2:42][CH3:43])=[CH:32][CH:33]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: [Cl-]
Reactant: CCc1cc(OC)ccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1
Agent: [Ca+2]
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(OC)ccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 401 mg (0.69 mmol) of (2S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-(2-ethyl-4-methoxyphenyl)pyridine-3-yl)propanoate in TFA (2.0 mL), protected from the atmosphere by a calcium chloride-filled drying tube was stirred at room temperature for two hours. The reaction mixture was concentrated in vacuo at less than 30° C. and the resulting orange oil was dissolved in ether to which a solution of 2 mL of 1 M HCl/ether was added. The resulting white solid was filtered and washed with ether to give the desired product as a white powder, 336 mg, 84% yield.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>C(=S)=S>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:10][CH:11]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: CC(=O)Nc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1290 g of aluminium chloride (9.6 mole) were suspended with stirring in 1500 ml of carbon disulphide. 405 g of acetanilide (3 moles) were added slowly to this suspension, while the temperature was kept at 25° C. The reaction mixture was heated until reflux and was cooled immediately to 25° C. 565 ml of propionyl chloride (6.5 moles) were added dropwise in such a way that the temperature was kept at 25° C. The reaction mixture was heated until reflux for 5 hours and kept overnight at ambient temperature (20° C.). The supernatant carbon disulphide layer was decanted and the remaining viscous mixture was poured in a mixture of ice and hydrochloric acid. The residue formed was filtered off and further recrystallized from a mixture of 1500 ml of ethanol and 75 ml of water. Drying was applied under vacuum at 100° C. A light yellow powder was obtained.
Reaction SMILES: Cl.[C:2]([N:6]1[CH2:10][CH2:9][CH:8](O)[CH2:7]1)([CH3:5])([CH3:4])[CH3:3].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][CH:8]1[CH2:9][CH2:10][N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)N1CCC(O)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)N1CCC(Cl)C1
Yield: 63.1 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of 1-t-butyl-3-pyrrolidinol (146 g, 1.02 mol) in chloroform (1.01) until the reaction mixture became acidic. A solution of thionyl chloride (1.55 g, 1.3 mol) was added dropwise with warming. After the addition was completed, the reaction mixture was stirred at reflux temperature for 18 h. The chloroform and excess thionyl chloride was removed on a rotary evaporator. Cracked ice and water was added to the residue and the mixture basified with 25% sodium hydroxide solution. The mixture was extracted with chloroform, and the extract washed with brine solution. The extract was dried (Na2SO4), concentrated and distilled at 75° C./15 mm to obtain 104 g (63%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[CH3:19][C:20]1([CH3:28])[C:25](=[O:26])[CH2:24][C:23](=O)[CH2:22][O:21]1>>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:3]3[C:4](=[O:8])[NH:5][N:6]([CH3:7])[C:2]=3[NH:1][C:23]3[CH2:22][O:21][C:20]([CH3:28])([CH3:19])[C:25](=[O:26])[C:24]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC1(C)OCC(=O)CC1=O
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)C(C)(C)OC1)C2c1ccc(F)c(Br)c1

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (339 mg, 3.0 mmol), 3-bromo-4-fluorobenzaldehyde (627 mg, 3.0 mmol), and the product from Example 43C (426 mg, 3.0 mmol) were processed as described in Example 22 to provide the title compound.
Reaction SMILES: [CH:1]1([CH:7]([O:49][C:50](=[O:53])[CH2:51][CH3:52])[O:8][P:9]([CH2:21][C:22]([N:24]2[C@H:32]([C:33]([O:35]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:34])[CH2:31][C:26]3([S:30][CH2:29][CH2:28][S:27]3)[CH2:25]2)=[O:23])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:7]([O:49][C:50](=[O:53])[CH2:51][CH3:52])[O:8][P:9]([CH2:21][C:22]([N:24]2[C@H:32]([C:33]([OH:35])=[O:34])[CH2:31][C:26]3([S:27][CH2:28][CH2:29][S:30]3)[CH2:25]2)=[O:23])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)OC(OP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2)C1CCCCC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)OC(OP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2)C1CCCCC1
Reaction time: 1.5 h
Yield: 158.4 %

Procedure:
A solution of 1.0 g (1.3 mmol) of (S)-7-[[[cyclohexyl(1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, benzhydryl ester in 10 ml of dichloromethane was stirred, cooled in an ice-bath, treated with 0.3 ml of anisole and 1.0 ml of trifluoroacetic acid (dropwise). After 90 minutes, the solvent and bulk of excess of trifluoroacetic acid were removed on a rotary evaporator and the residue was shaken with 50 ml of ethyl acetate and 20 ml of cold water. The layers were separated (5 ml of ether was added to break up the emulsion) and the organic phase was washed with three 20 ml portions of water. After back-extracting the combined aqueous layers with 25 ml of ethyl acetate, the combined organic layers were washed with 20 ml of saturated sodium chloride, dried (MgSO4), and the solvent evaporated to yield 1.26 g of a syrup. The syrup was purified by chromatography on 60 g of silica gel (60-200 mesh, d=0.37 g/ml) using 40:1:1 dichloromethane:methanol:acetic acid to give 0.74 g of a foam-like solid.