Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([C:31]([CH:33]4[CH2:35][CH2:34]4)=O)[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([CH2:31][CH:33]4[CH2:35][CH2:34]4)[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(C1CC1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(Oc2ccc3c(c2)[C@@]24CCCC[C@H]2[C@@H](C3)N(CC2CC2)CC4)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
To a suspension of 0.4 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran was added dropwise, 4.6 g (0.011 mol) of (-)-3-phenoxy-N-cyclopropylcarbonylmorphinan in 30 ml of anhydrous tetrahydrofuran over a period of 15 minutes. After the mixture had been refluxed under nitrogen for 16 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated. The residue was partitioned between ether and 4 N hydrochloric acid. The acidic phase was made basic with concentrated ammonium hydroxide and the aqueous suspension was extracted with ether. The ether solution was washed with water and dried. Removal of the ether under reduced pressure afforded 2.6 g (59%) of the product (-)-3-phenoxy-N-cyclopropylmethylmorphinan. For analysis, a sample of this compound was distilled, bp 190°200°/0.1mmHg, [α]25D -89.07° (c 0.99, MeOH).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([CH:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23]([OH:25])=O)[CH2:17]3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:23](=[O:25])[CH:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([NH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[NH:6][N:7]=[CH:8]3)[CH2:17]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH3:2]
Reactant: CCNCC
Reactant: O=C(O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
Diethylamine (35 mg) and the compound prepared in Example 222 (88 mg) were dissolved in dimethylformamide (1 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (77 mg), and dimethylaminopyridine (5 mg) were added to the solution. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give 58 mg of the title compound as a single diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]Br>C(OCC)C>[Br:12][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:11]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)cc1Cl

Procedure:
To 100 mL of ethyl ether is added 1-(2,4-dichlorophenyl)ethanone (18.9 g, 0.1 mol) and bromine (16 g, 0.1 mmol). Monitor the reaction by thin-layer chromatography. Upon completion wash the organic phase with 100 mL H2O and 50 mL brine. Dry the organic phase over Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]/[NH:11]C(OCC)=O)/[CH3:9])=[C:4]([CH3:17])[CH:3]=1.[S:18](Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:10]=[N:11][S:18][CH:9]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N/N=C(\C)c1ccc(Cl)cc1C
Product: Cc1cc(Cl)ccc1-c1csnn1
Temperature: 25 °C

Procedure:
Ethyl (2E)-2-[1-(4-chloro-2-methylphenyl)ethylidene]hydrazine carboxylate (0.63 g, 2.45 mmol) was stirred with thionyl chloride (1 mL, 13.70 mmol) at 60° C. for 1 h. The mixture was cooled to room temperature and concentrated in vacuo. 4-(4-Chloro-2-methylphenyl)-1,2,3-thiadiazole was obtained as a red solid. MS m/z=211.5; 1H NMR (CDCl3, 400 MHz) δ 2.45 (s, 3H), 7.31 (dd, J=2.2, 8.2 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 8.51 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:10][C:2]2[NH:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)[CH2:16][CH2:15]1)=[O:19]
Reactant: O=C(O)C1CCC(Cc2nc3ncccc3[nH]2)CC1
Reactant: NCc1ccccc1F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ncccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid (Compound AAB) (275 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol) and the resulting reaction mixture was stirred for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. Preparative chromatography eluting with chloroform:methanol gave the cis 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide as a white solid: mass spectrum m/z 367 [(M+H)+; calcd for C21H24N4OF: 366].
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(-n2ccnc2)cc1
Agent: Cl
Product: O=C(O)c1ccc(-n2ccnc2)cc1

Procedure:
Ethyl 4-(imidazol-1-yl)benzoate (0.5 g, 2.3 mmol) was heated at reflux in 5N HCl (40 ml) for 1 h, evaporated to dryness under reduced pressure and the resulting white solid dried in vacuo to afford 4-(imidazol-1-yl)benzoic acid This was suspended in dry toluene (40 ml) and thionyl chloride (2 ml) added under argon. The mixture was heated to reflux for 1.5 h and then evaporated to dryness under reduced pressure. The oil was dissolved in dichloromethane under argon and 4-methoxy-3-(4-methyl-1-piperazinyl)phenylamine (551 mg, 2.3 mmol) was added followed by triethylamine (2 ml). The mixture was stirred at room temperature under argon for 2 h and then partitioned between dichloromethane (50 ml) and saturated potassium carbonate (50 ml), and the organic extracts dried (sodium sulphate). The organic solution was filtered, evaporated to dryness under reduced pressure and purified by column chromatography (silica, chloroform/methanol 5-10%) to afford the amide (809 mg, 90%) which was crystallised from methanol diethyl ether as the oxalate salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1(Br)[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH3:13])=[O:6])[CH3:2].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH3:13])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C1(Br)CCOC1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)C1CCOC1OC
Yield: 98.1 %

Procedure:
Ethyl-2-(3-bromo-2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (8.5 g) was dissolved in Ethanol (85 ml). Triethyl amine (3.66 g) was added to the reaction mass. 5% Palladium on Carbon (0.85 g) was added and reaction was hydrogenated at 4-5 kg pressure of Hydrogen for 8 hrs. Reaction mass was filtered through hyflow and concentrated to residue. This residue was slurried in methyltert-butylether (42 ml) and filtered to remove triethylamine HBr salt. Filtrate was concentrated to get oily residue of Ethyl-2-(2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (yield 6.0 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:44])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:15](=[O:40])[N:16]([CH3:39])[CH:17]=[C:18]([C:20]3[C:21]([CH3:38])=[C:22]([NH:26][C:27]([C:29]4[S:33][C:32]5[CH2:34][CH2:35][CH2:36][CH2:37][C:31]=5[CH:30]=4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:19]=2)=[CH:9][C:8]=1[N+:41]([O-])=O)=[O:6].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:41][C:8]1[CH:9]=[C:10]([NH:13][C:14]2[C:15](=[O:40])[N:16]([CH3:39])[CH:17]=[C:18]([C:20]3[C:21]([CH3:38])=[C:22]([NH:26][C:27]([C:29]4[S:33][C:32]5[CH2:34][CH2:35][CH2:36][CH2:37][C:31]=5[CH:30]=4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:19]=2)[CH:11]=[CH:12][C:7]=1[C:5](=[O:6])[N:4]([CH2:3][CH2:2][OH:1])[CH3:44]
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N(C)CCO)c([N+](=O)[O-])c2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N(C)CCO)c(N)c2)n1
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid [3-(6-{4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-3-nitro-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide (5) (200 mg, 0.32 mmol) is dissolved in a mixture of ethanol (25 mL) and water (5.0 mL). Ammonium chloride (200 mg, 3.81 mmol) and iron powder (200 mg, 3.58 mmol) are then added and the reaction is allowed to proceed at 95° C. for 30 min. The reaction contents are then hot-filtered through celite and then transferred to a seperatory funnel with ethyl acetate (100 mL). The crude solution is then washed with saturated sodium bicarbonate (1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure. The resulting residue is then triturated with DCM and ethyl ether to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid [3-(6-{3-amino-4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide (6) as an off-white solid (135 mg), m/z 587.20 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].N[C:13]1N=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[CH3:11][C:7]1[CH:8]=[CH:9][N:10]2[C:15](=[O:16])[C:14]3[CH2:13][CH2:20][CH2:19][C:18]=3[N:1]=[C:2]2[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ncccc1C(=O)O
Reactant: Cc1ccnc(N)c1C(=O)O
Product: Cc1ccn2c(=O)c3c(nc2c1C(=O)O)CCC3

Procedure:
By substituting 2-amino-4-methylnicotinic acid for the 2-aminonicotinic acid in Example 4, there is obtained the named compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].C([Li])(C)(C)C.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[B:16]([OH:19])[OH:17]
Reactant: COB(OC)OC
Reactant: COc1cc(C)ccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
To a cooled (−78° C.) solution of 1-bromo-2-methoxy-4-methylbenzene (0.5 g; 2.49 mmol) in dry THF (12.5 mL) under argon atmosphere was added dropwise a tert-butyllithium solution (1.6M in pentane) (3.65 mL; 5.47 mmol). After 10 min, trimethyl borate (0.424 mL; 3.73 mmol) was added dropwise as a neat liquid and the reaction was stirred at −78° C. for 1 h. The reaction was allowed to warm up to room temperature and was stirred for another 1 h. The mixture was quenched with a saturated solution of ammonium chloride and the mixture was concentrated under reduced pressure. The residue was acidified with a solution of hydrochloric acid 2N and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was precipitated out off a mixture of dichloromethane-heptane, filtered, washed with heptane and dried under reduced pressure to afford 0.095 g (23%) of the title compound as an off-white solid.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].O>CO>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:28])[NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:5][CH:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: COCCN
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Solvent: O
Solvent: CO
Product: COCCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester (1.6 g) was dissolved in methanol (35 ml) and then, 2-methoxyethylamine (0.68 g) was added. And then, the reaction mixture was heated to reflux for 10 hours. The mixture was cooled, and after excess of water was added slowly to the solution at 35~40° C. to precipitate the crystals, the solution was slowly cooled again, stirred at 10° C. for 1 hour and filtered. The filtered solid was washed with a co-solvent (water:methanol=4:1, v/v) and was recrystallized using isopropanol and ether, filtered and dried to give 1.39 g (yield: 78%) of the desired compound. m.p.: 120~121° C.; 1H-NMR(CDCl3), ppm: δ 1.23(d, 6H), 3.15(m, 4H), 3.38(s, 3H), 3.55(m, 5H), 3.64(m, 2H), 3.91(m, 2H), 6.55(m, 1H), 6.90(m, 1H), 6.99(m, 1H), 7.49(m, 2H), 7.70(m, 1H), 7.81(m, 2H)
Reaction SMILES: [NH:1]([C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[O:28])[CH:21]=3)=[CH:16][CH:17]=2)[C:12]([Cl:42])=[CH:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)O.[OH-].[Na+]>FC(F)(F)C(O)=O>[C:2]1([NH:1][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[C:12]([Cl:42])=[CH:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)c(Cl)cn4C(=O)Nc3ccccc3)ccn2)CC1
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccc3c(c2)c(Cl)cn3C(=O)Nc2ccccc2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
After dissolving 260 mg of tert-butyl 4-{[(4-{[1-(anilinocarbonyl)-3-chloro-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Bicarbonate water and 5N aqueous sodium hydroxide were added, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 200 mg of N1-phenyl-3-chloro-5-[(2-{[(4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide as a faint yellow solid. After adding 0.5 ml of formaldehyde (37% in water), 170 mg of sodium triacetoxyborohydride, 50 mg of acetic acid and 5 ml of tetrahydrofuran to the solid, the mixture was stirred at room temperature for 10 minutes. Bicarbonate water and 5N aqueous sodium hydroxide were added, extraction was performed with ethyl acetate, and the extract was washed once with saline. The obtained ethyl acetate solution was passed through a glass filter coated with NH type silica gel. The silica gel was washed with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 210 mg of a faint yellow oil. The oil was solidified from a hexane and ethyl acetate mixed solvent to obtain 90 mg of a powder.
Reaction SMILES: [S:1]1[C:5]2([CH2:9][C@@H:8]([C:10]([OH:12])=[O:11])[NH:7][CH2:6]2)[S:4][CH2:3][CH2:2]1.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1.[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[S:1]1[C:5]2([CH2:9][C@@H:8]([C:10]([O:12][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:11])[NH:7][CH2:6]2)[S:4][CH2:3][CH2:2]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CC2(CN1)SCCS2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@@H]1CC2(CN1)SCCS2
Reaction time: 0.17 h

Procedure:
To a solution of (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, p-toluenesulfonate (6.0 g.) in 30 ml. of anhydrous dimethylformamide at 50 ° under argon is added a dimethylformamide solution of diphenyldiazomethane (3.6) portionwise. After 10 minutes at 50°, the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and precipitated with ether. The solvent is then decanted and the residue triturated with ethyl acetate/ether to give (S)-1,4-dithia-7-azaspiro [4.4]nonane-8-carboxylic acid, diphenylmethyl ester, p-toluenesulfonate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2(C(=O)O)CCCC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C1(c2ccc(CBr)cc2)CCCC1
Yield: 133.4 %

Procedure:
To a solution of 1-(4-methylphenyl)cyclopentane carboxylic acid tbutyl ester (2.00 g, 7.68 mmol) in CCl4 (80 mL) was added N-bromosuccinimide (1.37 g, 7.68 mmol) and benzoyl peroxide (0.050 g). This mixture was brought to reflux by heating, and maintained at reflux for 2 hours using a sun lamp (250 W). Additional N-bromosuccinimide (0.34 g, 1.9 mmol) was added, and after 20 minutes the solution was concentrated to 40 mL. The white precipitate was removed by filtration. The filtrate was concentrated to give 1-(4-bromomethylphenyl)cyclopentane carboxylic acid tbutyl ester (2.9 g, 100%) as a yellow oil which was used without additional purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32]([CH2:35][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])=[CH:14][CH:13]=1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(Nc1cccnc1)c1cc(CN2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Morpholine (0.05 ml, 0.57 mmol) and acetic acid (0.03 ml, 0.57 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared Example 82; 200 mg, 0.57 mmol) in DCE (5 ml) and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (181 mg, 0.86 mmol) was then added and the mixture was warmed to 50° C. overnight. Saturated sodium hydrogencarbonate (10 ml) was added and the mixture was stirred for 10 min before being diluted with dichloromethane (25 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (25 ml). The organics were combined and evaporated under reduced pressure. The residue was purified by MDAP to yield the title compound. 150 mg.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([C:24]([OH:26])=[O:25])[C:8]=1[S:27][C:28]([F:31])([F:30])[F:29].ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[NH2:6][C:7]1[N:11]([C:12]2[C:13]([Cl:23])=[CH:14][C:15]([C:19]([F:20])([F:21])[F:22])=[CH:16][C:17]=2[Cl:18])[N:10]=[C:9]([C:24]([OH:26])=[O:25])[C:8]=1[S:27]([C:28]([F:31])([F:30])[F:29])=[O:40]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1c(SC(F)(F)F)c(C(=O)O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: C#CC(N)=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: Nc1c(S(=O)C(F)(F)F)c(C(=O)O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 17 h
Yield: 80.4 %

Procedure:
To a suspension of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthio-I H-pyrazole-3-carboxylic acid propargylamide (0.71 g, 1.43 mmol) in dichloromethane was slowly added a solution of m-chloroperbenzoic acid (70%, 0.41 g, 1.68 mmol) in dichloromethane. After stirring for 17 hours at 20° C., an aqueous solution of sodium sulfite/sodium hydrogen carbonate (5%:5%, 25 ml) was added and stirring continued for 15 minutes. The aqueous phase was extracted with dichloromethane, dried over magnesium sulfate, evaporated and purified by flash chomatography (silica, heptane/ethyl acetate) to give the title compound (0.604 g, yield 86%) as white crystals, mp 207° C., 1H NMR (CDCl3): 2.28 (t, 1H, propargyl), 4.20 (m, 2H, propargyl), 5.17 (bs, 2H, NH2), 6.88 (bt, 1H, C(O)NH), and 7.83 (s, 2H, Ar—H).
Reaction SMILES: [Cl-:1].[C:2]([O:5][C:6]1[C:7]([CH3:22])=[C:8]2[C:13](=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:12][C:11]([CH3:21])([C:18](O)=[O:19])[CH2:10][CH2:9]2)(=[O:4])[CH3:3]>ClC1C=CC=CC=1>[C:2]([O:5][C:6]1[C:7]([CH3:22])=[C:8]2[C:13](=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:12][C:11]([CH3:21])([C:18]([Cl:1])=[O:19])[CH2:10][CH2:9]2)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Reactant: [Cl-]
Solvent: Clc1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2

Procedure:
To a mixture of 1.34 g. of dimethylchloroformimium chloride and 12 ml of chlorobenzene were added 2.92 g of (± )-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The resulting solution was heated at 110° under N2 for 40 min and stripped of solvent to give (±) 6-acetoxy-2,5,7,8 tetramethylchroman-2-carboxylic acid chloride as a light yellow, very viscous gum. To a mixture of 2.89 mmoles of this material in 4 ml of acetone was added 0.43 ml of triethylamine and 90 mg of 10% palladium on carbon catalyst. The mixture was hydrogenated at atmospheric pressure and room temperature. Uptake ceased after 1.0 hr. The suspension was filtered and the filtrate was stripped of solvent, taken up in ether, washed with saturated aqueous sodium bicarbonate solution, 2N aqueous HCl, and brine, dried over sodium sulfate and stripped of solvent. The residue was chromatographed on silica gel with 8:2 parts by volume benzene-ethyl acetate and then crystallized from 30°-60° petroleum ether to give (±)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxaldehyde as a white solid, m.p. 92.5°-96°.