Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[N:10][CH:11]=1)=[O:4].N#N.CO.C([Li])(C)(C)C.CN(C)[CH:26]=[O:27].Cl>C1COCC1.CCOCC.O>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[C:7]([CH:26]=[O:27])=[CH:8][C:9]([Cl:12])=[N:10][CH:11]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)nc1
Agent: Cl
Agent: N#N
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cnc(Cl)cc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A three-necked flask, equipped with a thermometer, a magnetic stirrer and a nitrogen inlet, was flushed with nitrogen. The flask was charged with 10.63 g of 2,2-dimethyl-N-(2-chloro-5-pyridinyl)propanamide (50 mmoles) and stoppered with a rubber septum. 100 Ml of THF was added to the flask. The flask was cooled in a liquid N2 /MeOH slush bath and 52.4 ml (110 mmoles) of 2.1M t-butyllithium was slowly added maintaining the temperature ≤75° C. by the rate of addition. The flask was transferred to a dry-ice/isopropanol (IPA) bath and stirred for 1.5 hours when a solution of 10.95 g (150 mmoles) of dimethylformamide in 5 ml of THF was added. The mixture was stirred at -78° C. for 30 minutes, 40 ml of 6N HCl was then added to the flask and the reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes at room temperature, water and ether were added and the organic layer was separated. The aqueous layer was washed twice with ether and the combined organic layers washed with saturated NaCl, dried over MgSO4 and evaporated to leave an oil. The oil was triturated sequentially with water and ether and filtered to remove precipitated solids. The ethereal filtrate was recovered and dried over MgSO4 and the ether evaporated. Chromatography of the oil residue by preparative liquid chromatography (eluting with 20% EtOAc (ethyl acetate)/hexane) gave 3.5 g of the aldehyde (29 % of theoretical) as a pale yellow solid. The solid was recrystallized from hexane to give yellow needles having a melting point of 105°-106.5° C. Carbon, hydrogen, nitrogen and chlorine content calculated for C11H13ClN2O is C, 54.89; H, 5.44; N, 11.64 and Cl, 14.73 percent by weight which compares to that actually found upon analysis of C, 54.79; H, 5.38; N, 11.63; and Cl, 14.74.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Li]C.C(=O)=O.CC(C)=O.[Cl:17][C:18]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([C:28](=[O:30])[CH3:29])=[CH:20][N:19]=1>CCOCC.Cl[Ti](Cl)(Cl)Cl>[Cl:17][C:18]1[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[C:21]([C:28]([OH:30])([CH3:1])[CH3:29])=[CH:20][N:19]=1
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C=O
Agent: [Li]C
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(O)c1cnc(Cl)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a 1.0 M solution of TiCl4 in toluene (6.67 mL, 6.67 mmol) was added a 1.6 M solution of MeLi in Et2O (4.18 mL, 6.69 mmol) dropwise a −78° C. (dry ice/acetone bath). The resulting dark solution stirred at −78° C. for 30 minutes. A solution of 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (500 mg, 2.23 mmol) in Et2O (3 mL) was added dropwise at −78° C. The reaction was slowly allowed to warm to rt in the dewar over a 15 h period. TLC analysis showed complete conversion to the more polar tertiary alcohol product. The mixture was then cooled to 0° C. and quenched with sat. aq. NH4Cl (10 mL) followed by EtOAc (10 mL) for the workup. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (2×10 mL). The EtOAc layers were combined, dried using Na2SO4 and evaporated to give the crude product. Purification using ISCO FCC eluting with 20% EtOAc in Hexanes gave 459 mg of 2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (86% yield) as a colorless oil. LC-MS MS (ESI) m/z 241.12 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 9.05 (s, 1H), 1.99 (s, 1H), 1.67 (s, 6H).
Reaction SMILES: O[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[NH+:8](COCC[Si](C)(C)C)[NH:9][CH:10]=[C:3]12.[Si]([C:23]#[N:24])(C)(C)C>C(Cl)Cl>[NH:8]1[C:4]2[C:3](=[N:2][C:7]([C:23]#[N:24])=[CH:6][CH:5]=2)[CH:10]=[N:9]1
Reactant: C[Si](C)(C)C#N
Reactant: C[Si](C)(C)CCOC[NH+]1NC=C2C1=CC=CN2O
Solvent: ClCCl
Product: N#Cc1ccc2[nH]ncc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 115.6 %

Procedure:
To a solution of 4-hydroxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridinium (1.59 g, 6 mmol) in DCM (130 mL) was added TMSCN (1.13 mL, 9 mmol). After 5 min at rt, (Me)2N(C(O)Cl (0.83 mL, 9 mmol) was added. The reaction mixture was stirred at rt for 4 days, after which it was diluted with DCM, washed with brine, and dried. Concentration followed by purification through column afforded 1H-pyrazolo[4,3-b]pyridine-5-carbonitrile (1 g, 61%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][CH2:15][N:14]2[CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[N:7][C:2]([C:28]4[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=4)=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 100 °C

Procedure:
In a two-neck flask was placed 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline, prepared as in STEP 3 above (2.33 g, 7 mmol, 1 equiv), 1-methylpyrazole-4-boronic acid pinacol ester (1.75 g, 8.4 mmol, 1.2 equiv), K2CO3 (3.86 g, 28 mmol, 4.0 equiv), and Pd(PPh3)4 (809 mg, 0.7 mmol, 0.1 equiv). The resulting mixture was degassed and refilled with N2 (3 times). 1,4-Dioxane/H2O (30 mL/6 mL) was added and the resulting mixture was heated at 100° C. for 3 h. The resulting mixture was poured into EtOAc/H2O (100 mL/100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator, and the resulting residue was purified by column using EtOAc as the eluent to yield the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:1][O:2][C:3]([CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:4]
Reactant: Brc1ccccc1
Reactant: COC(=O)C1c2ccccc2Nc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1c2ccccc2N(c2ccccc2)c2ccccc21
Reaction time: 2.5 h
Yield: 72.8 %

Procedure:
A solution of 1.00 g of acridan-9-carboxylic acid methyl ester (4.18 mmol), 0.44 mL of bromobenzene (4.18 mmol), 0.60 g of sodium t-butoxide (6.27 mmol), 23 mg of Pd(OAc)2 (0.105 mmol), and 17 mg of tri-t-butylphosphine (0.084 mmol) in 15 mL of toluene was stirred under inert atmosphere at room temperature. After 2.5 h, 5 g of silica gel in 15 mL of CH2Cl2 was added to the reaction mixture. The slurry was filtered, washed with excess CH2Cl2 and the filtrate was concentrated to a thick solution. 20 mL of hexanes was added to this solution, causing a white precipitate to form. The precipitate was filtered, washed with hexanes, and dried to afford 0.96 g of N-phenylacridan-9-carboxylic acid methyl ester (72%).
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].CN(C)[CH:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[N+:24]([O-])=O.[CH2:28](O)C.O>C1COCC1.ClCCl>[NH:24]1[C:16]2[C:15](=[CH:23][CH:22]=[C:18]([C:19]([O:21][CH3:28])=[O:20])[CH:17]=2)[CH:14]=[CH:13]1
Reactant: CCO
Reactant: CN(C)C=Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
Sodium dithionate (164.4 g; 16 equiv.) was added over a period of 20 minutes to a solution of 4-(2-(dimethylamino)vinyl)-3-nitrobenzoic acid (14 g; 1 equiv.) in a mixture of THF (42 ml), ethanol (42 ml) and water (140 ml). The reaction mixture was heated for 90 min. at reflux and then stirred for 12 hours at room temperature. When the conversion was complete, dichloromethane was added, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate. After removal of the solvent under reduced pressure, purification was carried out by column chromatography (silica gel, 10% ethyl acetate/hexane). Methyl 1H-indole-6-carboxylate (8 g; 40%) was obtained in the form of a solid.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:15]1([C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:24]O)[CH2:22][OH:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(F)(F)F.CCOCC.C(OC(C)C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:2]2([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:23][CH2:22][C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:24][O:1]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1
Reactant: OCC(CO)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(Cl)cc2)OCC(c2ccccc2)(c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
42.5 g (0.2 M) of ethyl 2-oxo-2-(4-chlorophenyl)acetate are placed in 400 ml of CH2Cl2 in a 500 ml reactor. 22.8 g (0.1 M) of 2,2-diphenylpropane-1,3-diol and then 14.2 g (0.1 M) of BF3.Et2O are added. The mixture is left to react with stirring for 72 h at room temperature. The reaction mixture is taken up in NaHCO3 solution. The organic phase is washed with saturated NaCl solution. After drying over Na2SO4 and concentration, a very thick oil is obtained. 150 ml of isopropyl ether are added and a white precipitate forms. After filtration, 30 g of product melting at 156-158° C. are obtained (yield: 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=O)[CH2:13][CH2:12]3)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)/[C:14](=[N:28]/[OH:29])/[CH2:13][CH2:12]3)[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)CCC4=O)c2)CCOC1C
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)CC/C4=N\O)c2)CCOC1C
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 66, 5-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenylthio}indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenylthio}indan-1-one oxime in 48% yield, m.p. 136°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH2:11][O:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[BrH:22]>C(O)(=O)C>[Br:22][CH2:11][CH2:12][CH2:13][C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([OH:10])=[O:14]
Reactant: O=C1OCCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 5.8 parts of 3,3-bis(4-fluorophenyl)tetrahydro-2H-pyran-2-one and 30 parts of a solution of hydrobromic acid in glacial acetic acid was stirred over week-end at room temperature. The reaction mixture was poured onto water. The precipitated product was filtered off and dissolved in 2,2'-oxybispropane. The organic phase was added with water, dried, filtered and evaporated. The residue was boiled in a mixture of 42 parts of 2,2'-oxybispropane and 42 parts of petroleum-ether. The product was filtered off and crystallized from 2,2'-oxybispropane, yielding 1.27 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid; mp. 161° C. (intermediate 22).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:30]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)/[CH:31]=[C:32](/[CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])\[CH3:33].[ClH:46]>O1CCOCC1.C(O)C.C(Cl)(Cl)Cl.C(OCC)C>[ClH:46].[CH2:30]([N:40]1[CH2:41][CH2:42][N:43]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:44][CH2:45]1)/[CH:31]=[C:32](/[CH2:34][CH2:35][CH:36]=[C:37]([CH3:38])[CH3:39])\[CH3:33]
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Reactant: CC(C)=CCC/C(C)=C/CN1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Reaction time: 5 h

Procedure:
1.0 Gram of 6-carboxy-3,4-dihydrocarbostyril, 1.3 g of DCC (dicyclohexylcarbodiimide) and 1.4 g of geranylpiperazine were suspended in 10 ml of dioxane, and the suspension was stirred at 60°-70° C. for 5 hours. After the reaction was finished, the solvent was removed from the reaction mixture by evaporation, then to the residue thus obtained was added a certain amount of diethyl ether and the crystals formed were removed by filtration. The mother liquor was concentrated, and the residue thus obtained was dissolved by adding chloroform, the chloroform solution was washed with water and an aqueous solution saturated with sodium chloride. The chloroform solution was dried with anhydrous sodium sulfate, then the solvent was removed by evaporation. To the residue thus obtained was added 20 ml of ethanol, and converted into hydrochloride with 1.3 ml of concentrated hydrochloric acid. Recrystallized from ethanol-water to obtain 340 mg of 6-(4-geranyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril.hydrochloride. monohydrate. Colorless needle-like crystals. Melting point: 265°-266° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C1C=CC=CC=1.Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>C1COCC1>[CH3:1][C:2]1([CH2:36][C:37]([O:39][CH3:40])=[O:38])[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: CC1SC(=O)NC1=O
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CC1(C)SC(=O)NC1=O
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 38.5 %

Procedure:
To a stirred solution of Compound 1d (300 mg, 2.3 mmol) in THF (20 mL) at −40° C. was added 2 M LDA in heptane/THF/benzene (2.4 mL, 4.8 mmol) dropwise. After 15 minutes, methyl 2-bromoacetate (0.30 mL, 3.2 mmol) was added and the reaction mixture stirred at −40° C. for 2 h then quenched by dropwise addition of AcOH (0.8 mL). The reaction mixture was diluted with EtOAc, and the organic portion washed with water (2×), brine (2×), dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to afford Compound 1e (180 mg, 39%) as a clear oil. LCMS=1.06 min using analytical method (B), 225.9 (M+Na). 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.24-2.84 (m, 2H), 1.81 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][CH:29]=[N:28][CH:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.CC1(C)C(C)(C)OB([C:39]2[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH:40]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>O.O1CCOCC1>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[NH:42]1[CH2:41][CH:40]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[C:19]([S:22]([NH:25][C:26]4[S:30][CH:29]=[N:28][CH:27]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]2=3)[CH2:44][CH2:43]1
Reactant: O=S(=O)(Nc1cncs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cncs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A microwave vial was charged with 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.076 g, 0.146 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2 H)-carboxylate (0.068 g, 0.219 mmol), Pd(AmPhos2)Cl2 (10.34 mg, 0.015 mmol), and potassium phosphate (0.093 g, 0.438 mmol). Dioxane (0.649 mL) and water (0.325 mL) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred at 50° C. for one hour. The reaction was concentrated and the material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetate (0.069 g, 0.108 mmol) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (br. s., 1 H), 8.81 (br. s., 2 H), 8.70 (s, 1 H), 7.81-7.75 (m, 1 H), 7.63 (s, 1 H), 7.58 (d, J=8.2 Hz, 1 H), 7.35 (s, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 7.06 (dd, J=2.1, 8.6 Hz, 1 H), 6.46 (d, J=8.6 Hz, 1 H), 5.86 (br. s., 1 H), 4.31 (d, J=4.1 Hz, 2 H), 3.66 (br. s., 2 H), 3.62 (t, J=4.1 Hz, 2 H), 3.17 (br. s., 3H), 2.42 (br. s., 1 H). m/z (ESI) 523.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][C:11]2[C:17]([CH3:18])=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[CH3:19])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:35].C([O-])(O)=O.[Na+].[Na+].[Cl-]>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][C:11]2[C:12]([CH3:19])=[CH:13][C:14]([NH:15][C:34](=[O:35])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:16][C:17]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2c(C)cc(N)cc2C)cc1Cc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cc(C)c(Cc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(C)c1
Reaction time: 4 h
Yield: 53.5 %

Procedure:
335 mg (0.96 mmol) of 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylaniline (Example X) and 107 mg (1.06 mmol) of triethylamine are introduced into ml of dichloromethane and, at 0° C., 177 mg (1.29 mmol) of ethoxalyl chloride are added dropwise. The mixture is stirred for 4 h. It is shaken with NaHCO3 solution and NaCl solution, and the organic phase is dried and concentrated in a rotary evaporator. Purification by chromatography (cyclohexane/ethyl acetate=7:1) affords 231 mg of ethyl ({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl}amino)(oxo)-acetate.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Clc1cnccn1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(c3cnccn3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=564.3 (M+H+), was prepared in accordance with the general method of example 59 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 2-chloropyrazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:20][C:19]([C:21]([O:23]CC)=[O:22])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O.C(#N)C.CCOC(C)=O.OS([O-])(=O)=O.[K+]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2ccccc2CNC(=O)OC(C)(C)C)s1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 5-(2-{[(tert-butoxycarbonyl)-amino]methyl}phenyl)thiophene-2-carboxylate (2.05 g, 5.67 mmol) and lithium hydroxide (0.679 g, 28.4 mmol) in water (20 mL) and ACN (20 mL) was allowed to stir at rt for 24 h. The reaction mixture was diluted with EtOAc and 1N KHSO4. The organic solution was removed and the aqueous mixture was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered, and concentrated. The residue was dried under vacuum to give 5-(2-{[(tert-butoxycarbonyl)amino]methyl}phenyl)thiophene-2-carboxylic acid (1.71 g, 90%) as a white solid which was used without purification. LCMS: (FA) ES-332.3.
Reaction SMILES: C([N:4]([CH:7]([CH3:9])C)[CH2:5][CH3:6])(C)C.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C:18]([N:4]1[CH2:5][CH2:6][CH:12]([CH2:11][CH2:10][OH:17])[CH2:9][CH2:7]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Temperature: 0 °C

Procedure:
A solution of 3-1 (Aldrich) (25 g, 0.94 mol) in THF (400 mL) was treated with diisopropylethylamine (67 mL, 0.388 mol) and cooled to 0° C. under argon. Benzylchloroformate (27.6 mL, 0.194 mol) was added and the reaction was allowed to warm to room temperature. The reaction was concentrated, the residue was diluted with Et2O (300 mL), washed with water, 10% KHSO4 solution and brine, dried (MgSO4), filtered and evaporated to give 3-2 as an oil. Rf (35% EtOAc/Hexanes) 0.08 1H NMR (300 MHz, CDCl3) δ 7.38 (s, 5H), 5.13 (s, 2H), 4.18 (b, 2H), 3.7 (dd, 2H), 2.8 (bt, 2H), 1.78 (bd, 2H), 1.5 (m, 2H), 1.4 (m, 1H), 1.2 (m, 2H).