Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl[Sn]Cl.[OH-].[Na+]>O>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 36 °C

Procedure:
A 3-L 3-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with (4-chlorophenyl)(4-nitrophenyl)methanone (132.0 g, 504.5 mmol), concentrated aqueous HCl (693.3 mL, 8.1 mol), and SnCl2 (313.3 g, 1.62 mol). The yellowish suspension was carefully heated to 36° C. with fast agitation (1000 rmp). The electric power to the heating mantle was turned off at 36° C. A moderate exotherm was observed, which gradually increased to 77° C. over 1 h with gas evolution to form a foamy suspension. The electric power was turned on at 77° C. again and gradually heated to 100° C. over 30 min and refluxed for 2 h. The reaction was cooled to 10° C., slowly poured into a mixture of ice (1 L) and 33% NaOH (1 L, 8.25 M) with fast stirring in an ice-water bath. The resulting yellowish slurry (pH=2-3) was adjusted to pH=9-10 with 50% NaOH. The resulting solid was collected by filtration and washed with deionized water (100 mL). The filtration cake was dried under air-suction at 20° C. overnight and then in a vacuum oven at 60° C. for 24 h to yield a yellowish solid. The yellowish solid (322 g) was suspended in deionized water (2 L) and extracted with EtOAc (2 L×3). The combined organic phases were washed with brine (1 L/each). The solvent was concentrated at 60° C. to yield (4-aminophenyl)(4-chlorophenyl)methanone as a slightly yellowish crystalline solid. (ES, m/z) 232, 234 (M+H)+
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH:9]12[CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH:13]1[CH2:14][CH2:15][NH:8]2
Reactant: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2CCNC2C1

Procedure:
21.2 g (77.3 mmol) of ethyl 2-benzyl-2,7-diazabicyclo [3.3.0]octane-7-carboxylate in 400 ml of ethanol are hydrogenated at 100° C. and 100 bar on 3 g of palladium-active carbon (10% Pd). The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[OH:16][C:17]1([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[N:36][OH:37])[NH2:35])=[CH:30][CH:29]=2)[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1.[Cl:38][C:39]1[CH:40]=[C:41]([C:46]2([CH2:52][CH2:53][C:54](O)=O)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:42]=[C:43]([Cl:45])[CH:44]=1.C(N(C(C)C)CC)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:38][C:39]1[CH:40]=[C:41]([C:46]2([CH2:52][CH2:53][C:54]3[O:37][N:36]=[C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:17]5([OH:16])[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]5)=[CH:29][CH:30]=4)[N:35]=3)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: O=C(O)CCC1(c2cc(Cl)cc(Cl)c2)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(C(N)=NO)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(-c3noc(CCC4(c5cc(Cl)cc(Cl)c5)CCCCC4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
BOP-Cl (36.4 mg, 0.143 mmol) was added to a mixture of crude tert-butyl 3-hydroxy-3-(4-(N′-hydroxycarbamimidoyl)phenyl)azetidine-1-carboxylate (Intermediate 4, 40 mg, 0.13 mmol), 3-(1-(3,5-dichlorophenyl)cyclohexyl)propanoic acid (39.2 mg, 0.13 mmol) and diisopropylethyl amine (0.045 mL, 0.26 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 2 h, and a 1M solution of tetra-n-butylammonium fluoride in THF (0.13 mL, 0.13 mmol) was added. The mixture was heated to 80° C. overnight, diluted with ethyl acetate, and washed with saturated aqueous NaCl solution. The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified on a 24 g ISCO cartridge and eluted with EtOAc-hexanes gradient to obtain tert-butyl 3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate (56 mg, 50% yield, HPLC purity: 80%). HPLC retention time=4.71 minutes (Waters Sunfire C18 4.6×50 mm) eluting with 10-90% aqueous methanol with 0.1% TFA over a 4 minute gradient. LC/MS: m/e 572.25 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.O.O.[C:8]([O-:16])(=[O:15])[C@H:9]([CH2:11][C:12]([O-:14])=[O:13])[OH:10].[Ca+2]>>[C:8]([OH:16])(=[O:15])[C@H:9]([CH2:11][C:12]([OH:14])=[O:13])[OH:10]
Reactant: O=C([O-])C[C@H](O)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
30 g of the immobilized preparation of Brevibacterium ammoniagenes IAM 1645, obtained in the same manner as described in Example 1-(1), are suspended in 100 ml of an aqueous 1 M sodium fumarate solution (pH 7.5) containing 3 mg/ml of ox bile extract (manufactured by Inolex Pharmaceutical Division Wilson Pharmaceutical & Chemical Corporation, Illinois, U.S.A.). The suspension is allowed to stand at 37° C. for 20 hours, and is then filtered. The immobilized preparation thus obtained is washed with a physiological saline solution and charged into a column (2.2 cm×19.5 cm). One liter of an aqueous 1 M sodium fumarate solution(pH 7.5) is passed through the column at 37° C. at a flow rate of 20 ml/hr. The effluent is acidified with 200 ml of concentrated hydrochloric acid, and then filtered to remove the precipitates of fumaric acid. The filtrate is adjusted to pH 6.0 with about 70 g of calcium hydroxide. The crystalline precipitates are collected by filtration, washed with water and then dried. 150 g of calcium L-malate dihydrate are thereby obtained. 350 ml of 2N-sulfuric acid are added to calcium L-malate dihydrate. The mixture is filtered to remove the precipitates. The filtrate is passed through a column charged with about 150 ml of Amberlite IR-120(H+ type) and then passed through a column charged with about 150 ml of Amberlite IR-45 (OH- type). The effluent is concentrated at 60° C. under reduced pressure. The crystalline precipitates are collected by filtration, washed with a small amount of acetone and then dried. 50 g of L-malic acid are thereby obtained. The mother liquor is concentrated and the concentrated solution is treated in the same manner as above. 22 g of L-malic acid are thereby obtained. Total amount 77 g M. P. 100° C. [α]D20 =-2.2°(C=8.5, H2O)
Reaction SMILES: N[C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)[C:8]=2C)[N:3]=1.[CH3:28]N(C=NC1N=C(N=CN(C)C)C2C(=CC=C(C3C=C(C(F)(F)F)C=C(C(F)(F)F)C=3)C=2C)N=1)C>COC(OC)N(C)C>[CH3:28][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:17]=[C:16]([C:24]([F:26])([F:25])[F:27])[CH:15]=3)[CH:8]=2)[N:3]=1
Reactant: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc2nc(N)nc(N)c12
Reactant: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc2nc(N=CN(C)C)nc(N=CN(C)C)c12
Agent: COC(OC)N(C)C
Product: Cc1ncc2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2n1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.0 gram (0.0026 mole) of 2,4-diamino-5-methyl-6-[3,5-di(trifluoromethyl)phenyl]quinazoline (Compound 63-prepared as in Example 1) in 20 mL of dimethylformamide dimethyl acetal was heated at 80° C. for about 18 hours. After this time, the reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was then triturated with petroleum ether, and the resulting solid was collected by filtration. The filter cake was washed with petroleum ether and dried, yielding about 1.1. grams of 2,4-di(dimethylaminomethyleneamino)-5-methyl-6-[3,5-di(trifluoromethyl)phenyl]quinazoline, mp 208°-210° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>ClCCl>[C:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCOC(=O)C(=Cc1ccccc1Br)C(=O)OCC
Reactant: C#CCCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(C(=O)OCC)C(=O)OCC
Yield: 62.9 %

Procedure:
Reaction of diethyl 2-(2-bromophenyl)methylenepropan-1,3-dioate (6.54 g, 20 mmole, from example 1) with 1-tridecyne (6.1 g, 34 mmole) as described in example 3 gave 5.37 g (63%) of the title compound after chromatography on silica gel eluting with dichloromethane: petroleum ether [bp 60°-80° C.] (1:1). It had, νmax (film) 1730, 2850, 2920 cm-1, δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.13-1.68 (24H, m, ester CH3 +alkylene chain), 2.42 (2H, t, J 6.3 Hz, ≡--CH2), 4.23 (2H, q, J 7.5 Hz, ester CH2), 4.26 (2H, q, J 7.5 Hz, ester CH2), 7.31 (4H, m, aromatics), 8.20 (1H, s, CHO), M+ 426.2780 (C27H38O 4 requires; 426.2770).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:15][C:14]=1F)(=[O:12])=[O:11].[CH3:32][O-:33].[Na+]>CO.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:15][C:14]=1[O:33][CH3:32])(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2F)c(C)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OCC2CCOCC2)ccc1S(=O)(=O)N(CC(C)C)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-2-fluoro-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (358 mg, 0.478 mmol) in methanol (1 mL) at room temperature was added 25% sodium methoxide in methanol (109 uL, 0.478 mmol). The reaction mixture was stirred at room temperature for 2 hours, then heated to reflux for 1 hour. The reaction was quenched with water (1 mL) and the solvents removed in vacuo to give a yellow solid. The crude residue was dissolved in dichloromethane (DCM) (10 mL) and the organics washed with water (3×10 mL). The organics were passed through a hydrophobic frit and the filtrate evaporated to dryness to give a yellow oil. The crude was purified by mass directed autoprep (ammonium carbonate modifier). The solvent was evaporated under a stream of nitrogen to give the required product, 129 mg. LCMS [LCMS2] Rt 1.47 min, m/z (ES+) 462 (M+H).
Reaction SMILES: O=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6]CC)=O.C1(NN)CCCCC1.[CH:19]1([C:22]2[N:26]([CH:27](C)C)[N:25]=[CH:24][C:23]=2C=O)[CH2:21][CH2:20]1>>[CH:24]1([N:25]2[C:2]([CH2:9][CH3:10])=[C:3]([CH:4]=[O:6])[CH:27]=[N:26]2)[CH2:20][CH2:21][CH2:19][CH2:22][CH2:23]1
Reactant: CCOC(=O)CC(=O)CC
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: NNC1CCCCC1
Product: CCc1c(C=O)cnn1C1CCCCC1

Procedure:
1-Cyclohexyl-5-ethyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-pentanoate and cyclohexyl hydrazine (TCI) in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([C@@H:20]3[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:16]=2)=[CH:11][CH:10]=1.[F:33][C:34]([F:47])([F:46])[O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([S:42]([C:39]4[CH:38]=[CH:37][C:36]([O:35][C:34]([F:33])([F:46])[F:47])=[CH:41][CH:40]=4)(=[O:44])=[O:43])[CH2:22][CH:21]3[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccc([C@@H]2CNCC[C@H]2c2cc(-c3ccc(Cl)cc3)[nH]n2)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(c2cc(-c3ccc(Cl)cc3)[nH]n2)C(c2ccc(F)cc2)C1
Temperature: 60 °C

Procedure:
The product from Example 8 (23 mg, 0.049 mmol) in pyridine (1.0 ml) was treated with 4-trifluoromethoxybenzenesulfonyl chloride (63.8 mg, 0.245 mmol). The reaction mixture was heated to 60° C. for 12 h. The mixture was then concentrated and purified by RP-HPLC(C18, acetonitrile, water, 0.05% TFA) to afford the title compound. HPLC/MS: 580.0, 582.1; Rt=2.33 min (LC-4 HPLC conditions).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.N1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH:8]([CH:4]1[O:3][C:2]([N:1]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][C:5]1=[O:7])([CH3:10])[CH3:9]
Reactant: CC(C)C1OC(N)=NC1=O
Reactant: C1COCCN1
Product: CC(C)C1OC(N2CCOCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and morpholine according to Method G+H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(C)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.4 %

Procedure:
1-(5-Chloro-2-methoxyphenyl)ethanol (Preparation 4, 6.97 g, 37.3 mmol), was dissolved in trifluoroacetic acid (20 mL). Triethylsilane (29.8 mL, 187 mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with water. The organic phase was separated and concentrated in vacuo to afford the title compound (9 g, 141%, contains residual triethylsilane). This material was taken on crude in subsequent steps.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:35])[CH2:33]Br)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:35])[CH2:33][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: O=C(CBr)N[C@H]1CCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)N[C@H]2CCN(Cc3ccccc3)C2)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
(S)-(+)-1-Benzyl-3-aminopyrrolidine (6 g, 34 mmol) was dissolved in dichloromethane (12 ml). To this solution, a solution of bromoacetyl chloride (5.46 g, 34 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 7.3 g (64%) of (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step. 4-Hydroxy-2-methoxybenzaldehyde (2.39 g, 16 mmol) was dissolved in DMF (10 ml) and potassium carbonate (7.3 g, 52 mmol) was added followed by a suspension of the above (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.5 g, 10 mmol) in DMF (20 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were washed with saturated sodium chloride (3×15 ml), dried (MgSO4) and concentrated in vacuo. The residue (4 g) was crystallised from a mixture of diethyl ether and heptane, filtered and dried in vacuo to afford 2.7 g (71%) (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)-acetamide as a solid. M.p.: 96-100° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](O)(=[O:11])/[C:7](=[CH:9]/[CH3:10])/[CH3:8]>C(Cl)Cl>[CH3:10][CH:9]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[C:6](=[O:11])[CH:7]1[CH3:8]
Reactant: c1ccsc1
Reactant: C/C=C(\C)C(=O)O
Solvent: ClCCl
Product: CC1C(=O)c2sccc2C1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To polyphosphoric acid (prepared from 500 g of P4O10 and 340 g of 85% H3PO4), a mixture of 47.6 ml (50.0 g, 0.60 mol) of thiophene and 59.5 g (0.60 mol) of tiglic acid in 80 ml of CH2Cl2 was added over 2.5 hours at 50° C. This mixture was stirred at this temperature for 2 hours, and then immersed in 1 kg of ice. The product was extracted with 3×300 ml of methyl-tert-butyl ether. The combined extract was washed with a saturated aqueous solution of Na2CO3, dried over K2CO3, and evaporated to dryness. Fractional distillation gave a colorless oil, bp 96-98° C./2 mm Hg. Yield 89.3 g (90%). On the evidence of NMR spectroscopy, the product was a mixture of two diastereomers (ca. 3:1).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C:17]1([CH2:23][C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CC(N(C)C)=O>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(Cc1ccccc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
To a 4 mL vial was added the product from Example 11B (20 mg in DMA), phenylacetic acid [1.5 equivalents in dimethyl acetamide, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2 equivalents in dimethyl acetamide) and triethylamine (3 equivalents, neat). The vial was capped and microwaved at 150° C. for 30 minutes. The reaction was checked by LC/MS and concentrated to dryness upon completion. The residue was dissolved in 1:1 MeOH:DMSO and purified by reverse phase HPLC [Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min [0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A]. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.89-11.91 (bs, 1H), 8.43 (dd, J=8.0, 1.3 Hz, 1H), 8.12-8.15 (m, 1H), 7.96-8.08 (m, 2H), 7.32-7.42 (m, 4H), 7.26-7.30 (m, 1H), 3.73 (s, 2H); MS (ESI+) M/Z 348 (M+H)+, 365 (M+NH4)+.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>C1(C)C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2)cc1OC
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc(OC)c(OC)c1
Yield: 93.4 %

Procedure:
21.6 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine (cf. Example 2) are dissolved with 5.2 g of triethylamine in 200 ml of dry toluene. Then a solution of 5.4 g of chloroformic acid ethyl ester in 50 ml of toluene is added dropwise with stirring. Thereafter, the mixture is stirred for a further two hours. After filtration, the filtrate is washed free of halide with water and evaporated to dryness. A yellowish oil, which is recrystallized from diisopropyl ether, is obtained as the residue. 22.7 g (94 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-carbethoxy-piperazine are obtained. m.p. = 113° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20](=[O:22])[CH3:21])(=[O:3])[CH3:2].C[N:24]([CH3:27])C=O.[C-]#N.[K+].OS(O)(=O)=O>O>[C:27]([C:20]([OH:22])([CH2:19][CH2:18][C:6]1[C:7]([CH3:17])=[C:8]([O:13][C:14](=[O:16])[CH3:15])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=1[O:4][C:1](=[O:3])[CH3:2])[CH3:21])#[N:24]
Reactant: CN(C)C=O
Reactant: CC(=O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Agent: O=S(=O)(O)O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(CCC(C)(O)C#N)c1C
Reaction time: 0.17 h

Procedure:
A solution of the crude 4-(2,5-diacetoxy-3,4,6-trimethylphenyl) butan-2-one prepared in Example 56 in 963 ml. of dimethylformamide was cooled under N2 in an ice bath. A solution of 69.4 g. of potassium cyanide in 150 ml. of H2O was added over 20 minutes. The mixture was stirred another 10 minutes and then 161 ml. of 6N H2SO4 was added dropwise over 20 minutes while an internal temperature of +10° to +13° was maintained. The viscous suspension (pH 8) was stirred another 30 minutes, brought to pH 4 by the addition of 16.5 ml. of 6N H2SO4, poured into ice-H2O, and extracted with ether. The ether solutions were washed with brine, dried over Na2SO4, and stripped of solvent to give (±)-2-cyano-4-(2,5-diacetoxy-3,4,6-trimethylphenyl)butan-2-ol as an orange-brown foam.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][C:31]=4[F:40])[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.CO.[OH-].[K+].Cl>O1CCCC1.C(OCC)(=O)C>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:18])([F:17])[F:19])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:23][CH:24]3[N:29]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]=4[F:40])[CH:27]([CH2:26][CH2:25]3)[CH2:28]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)(F)F)noc2C2CC2)C3)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)(F)F)noc2C2CC2)C3)c(F)c1
Temperature: 70 °C

Procedure:
The ester above, methyl 4-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzoate (24 mg, 0.043 mmoles) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) and subjected to an aqueous solution of potassium hydroxide (6 N aqueous solution, 0.5 mL, 3.0 mmoles). The mixture was heated to 70° C. for 2 hours and then cooled to RT. The pH of the solution was adjusted to 6 using aqueous HCl (0.5 mL of 6N). The mixture was diluted with ethyl acetate (20 mL), extracted and water washed (3×1 mL). The organics were dried (MgSO4) then evaporated in vacuo. The product crystallized upon concentration of the ethyl acetate mother liquor, was washed with sparing ice cold ethyl acetate (0.5 mL), and the white solid dried to give the title compound.