Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl>C(Cl)Cl>[CH3:21][S:22]([O:11][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:1])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCC(C)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCC(C)OS(C)(=O)=O
Reaction time: 0.17 h
Yield: 105.8 %

Procedure:
To a solution of 2-decanol (5.0 ml, 26.0 mmol) in dry CH2Cl2 (52 ml) under an N2 atmosphere was added diisopropylethylamine (5.6 ml, 32.1 mmol). The reaction flask was immersed in an ice/water bath. After stirring for 10 minutes, methanesulfonyl chloride (2.8 ml, 36.1 mmol) was added via syringe over a period of 10 minutes. After stirring for 3 hrs, the reaction was diluted with cold CH2Cl2 (200 ml) and poured into cold 5% aqueous HCl (100 ml). The layers were separated and the organic phase washed with cold 5% aqueous HCl (50 ml) followed by brine (2×50 ml). The CH2Cl2 layer was dried (Na2SO4), filtered and evaporated in vacuo at 25° C. The resulting light yellow oil was pumped under reduced pressure for 2 hrs to provide 2-methanesulfonyloxydecane (6.5 g, 93.5%) as a light yellow oil.
Reaction SMILES: [CH:1]([C:3]([OH:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]>[Pd].C1CCCCC1>[CH2:1]([C:3]([OH:16])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: C=CC(O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCCCC1
Product: CCC(O)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 21 g. of α-vinyl-benzhydrol and 84 ml. of cyclohexane is refluxed in the presence of palladium catalyst. When the reaction is over, as evidenced by thin layer chromatography, the mixture is cooled, the catalyst is filtered off, and the filtrate is evaporated under reduced pressure. 21.2 g. of crystalline α-ethyl-benzhydrol, melting at 93°-94° C, are obtained as residue.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=O)[CH2:27][CH2:26]2)=[O:22])[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:39][OH:40]>C(O)C.O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:10]([F:11])([F:13])[F:12])[C:14]([F:15])([F:17])[F:16])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[N:39][OH:40])[CH2:27][CH2:26]2)=[O:22])[CH3:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(c1)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(c1)CCC2=NO
Yield: 92.8 %

Procedure:
N-[2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-1-oxoindane-5-carboxamide (2.4 g) was dissolved in ethanol (40 ml), and sodium acetate (0.85 g) and hydroxylamine hydrochloride (0.43 g) were added thereto, and then stirred and heated at reflux temperature for 2 hours. The reaction solution was brought back to room temperature and diluted with water. The resulting crystals were collected by filtration and dried to obtain N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-1-(hydroxyimino) indane-5-carboxamide (2.3 g, yield 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH:12]([CH2:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:12]([CH2:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: CCCC(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1O
Product: CCCC(Oc1ccccc1[N+](=O)[O-])C(=O)OCC
Yield: 104.1 %

Procedure:
Starting from 2-nitrophenol (1.0 g, 1 eq, 7.19 mmol) and ethyl 2-bromopentanoate (2.97 ml, 3.0 eq, 21.54 mmol) the procedure of step (i), preparation 17 was followed to obtain ethyl 2-(2-nitrophenoxy)pentanoate (2.0 g) as crude which was used for step (ii).
Reaction SMILES: [NH4+].[Cl-].[N+:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)([O-])=O>CO.O.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Oc2ccccc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Fe (2.9 g, 52.4 mmol, 4.0 eq) and NH4Cl was added to a solution of 6-nitro-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile (5.0 g, 13.1 mmol, 1.0 eq) in methanol/water (50/50 mL). The mixture was heated to reflux for 8 hours, cool to room temperature and extracted with ethyl acetate (100×3 mL). The organic layers were combined, dried over anhydrous sodium sulfate. The crude product was purified by flash column chromatography on silica gel to give 6-amino-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile (Compound 19) as a solid 3.5 g.
Reaction SMILES: N[C:2]([NH2:4])=[O:3].[F:5][C:6]1[CH:7]=[C:8]2C(=O)O[C:10](=[O:11])[C:9]2=[CH:15][CH:16]=1>>[F:5][C:6]1[CH:16]=[C:15]2[C:2](=[O:3])[NH:4][C:10](=[O:11])[C:9]2=[CH:8][CH:7]=1
Reactant: NC(N)=O
Reactant: O=C1OC(=O)c2cc(F)ccc21
Product: O=C1NC(=O)c2cc(F)ccc21
Temperature: 160 °C
Reaction time: 3 h

Procedure:
8.2 parts (0.137 mole) of urea are added to 185 parts of the distillate (containing 43.4 parts (0.261 mole) of 4-fluorophthalic anhydride). The mixture is stirred for 3 hours at 135°-140° C., after which the evolution of gas is complete, and is finally heated for a further 10 minutes at 160° C. The solvent is distilled off (144.2 parts) at 115°-130° C. and under 0.3 mbar. According to gas chromatography, it contains 9.6 parts of 4-fluorophthalimide. The distillation residue is stirred with water, and the product is filtered off under suction, washed and dried, 31 parts of 4-fluorophthalimide of melting point 174°-176° C. being obtained. The total yield is 40.6 parts (94.2% of theory) of 4-fluorophthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH3:24]>>[Cl:22][C:21]1[C:16]([Cl:15])=[C:17]([O:23][CH3:24])[CH:18]=[CH:19][C:20]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:5]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccccc2Cl)c(Cl)c1Cl

Procedure:
The Friedel-Crafts procedure of Example 24a is repeated with 48.13 g of o-chlorobenzoyl chloride being combined with 36.7 g AlCl3 and 44.26 g of 2,3-dichloroanisole to yield a white crystalline product of 2,3-dichloro-4-methoxy-2'-chlorobenzophenone, mp 117°-120° C.
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].CS([C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH2:1]([C:4]1[O:5][C:6]([C:10]2[C:15]([O:16][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)c(-c2c(O)cccc2Cl)o1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(-c2c(Cl)cccc2Oc2nc(OC)cc(OC)n2)o1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
2 ml DMF solution containing 0.24 g 2-propyl-4-methyl-5-(2-chloro-6-hydroxyphenyl)oxazole, 0.2 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.26 g pottasium carbonate was stirred for 14 hours at 60° C. After completing the reaction, the solution reacted was poured into ice water and was then extracted with ethyl acetate. The organic layer obtained was washed with water and was then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduce pressure. The residue obtained was purified by using silica gel column chromatography, where hexane-ethyl acetate solution in a mixing ratio of 4:1 is used, affording the objective substance in an amount of 0.26 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](C(=O)NCc3nccnc3Cl)CC2)CC1

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (40.7 mmol, 10.9 g) in dichloromethane (145 ml) and acetic acid (1.450 ml) at room temperature was added 1-methylpiperazine (52.9 mmol, 5.87 ml, 5.30 g) and sodium cyanoborohydride (81 mmol, 5.12 g). After 16 hours at room temperature dichloromethane and an aqueous saturated sodium hydrogencarbonate solution (15 mL) were added and the organic layer was separated. This organic layer was washed with brine. The aqueous layers were washed with dichloromethane twice and the combined organic extracts dried (sodium sulfate). Concentration in vacuo gave the crude product (mixture of cis and trans), which was purified using column chromatography (silica gel; dichloromethane/methanol gradient (0 to 20% methanol) to afford the cis isomer (275 mg), the trans isomer (2.5 g) and a mixture of cis and trans isomers (5.5 g).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>ClCCl>[CH3:35][O:34][C:32]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:15][CH:14]=[C:13]([C:11]([N:1]3[C@@H:10]4[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:4][CH2:3][CH2:2]3)=[O:12])[CH:17]=2)[CH2:23][CH2:22]1)=[O:33]
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 2 h
Yield: 49.1 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.04 g, 0.12 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (0.37 mmol). Methyl chloroformate (0.25 mmol) was added and the mixture stirred for 2 hours and then the solvent removed by evaporation. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.023 g). LCMS m/z 391.15 min [M+H]+ RT=11.55 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.6 (m, 1H), 4.3 (m, 2H), 3.8 (m, 1H), 3.7 (s, 3H), 3.1-2.7 (m, 4H), 2.1-1.1 (m, 17H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:41][CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>CN(C)C=O>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:41][CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.5 g) in dimethyformamide (20 ml) are added potassium carbonate (0.6 g), potassium iodide (0.72 g) and 2-(3-bromopropyloxy)-3,4,5,6-tetrahydro-2H-pyrane (0.97 g) and the mixture is stirred at room temperature overnight. The reaction solution is concentrated and to the resulting residue is added water. The mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1) to give 5-{N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.3 g) as colorless amorphous.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[CH2:19]1[CH2:23]OC[CH2:20]1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[C:20]#[C:19][CH3:23])=[CH:17][CH:18]=1
Reactant: C1CCOC1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Reaction time: 0.25 h

Procedure:
An oven-dried 3L 3-neck flask equipped with a mechanical stirrer, nitrogen inlet, nitrogen outlet and placed in a room-temperature water bath. After purging with nitrogen for 20 minutes, a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) was added by cannula. In a separate oven-dried and nitrogen-flushed 500 mL RB flask, compound 1.1 (35 g, 142 mmol) was dissolved in anhydrous THF (350 mL) with gentle warming. The solution of 1.1 was then added over 15 minutes. Over the course of the addition, the reaction mixture changed to a thick, yellow suspension. After the addition was complete, the reaction mixture was stirred for 15 minutes and then quenched with aqueous NH4Cl (0.6N, 750 mL) and diluted with hexanes (800 mL). The layers were separated and the organic layer discarded. The aqueous layer was acidified to pH ˜2 with saturated aqueous KHSO4 and extracted with ethyl acetate (2×400 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (37 g, 91%). 1H NMR(500 MHz)(acetone-d6) δ 8.26 (s, 1H); 7.39 (d, 2H, J=8.5 Hz); 6.76 (d, 2H, J=8.4 Hz); 4.73 (br s, 1H); 4.46 (d, 1H, J=2.4 Hz); 1.82 (s, 3H); 1.81 (s, 3H); 1.64 (s, 3H). MS ESI (pos.) m/e: 599.0 (2M+Na).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([NH:19][CH3:20])[CH:16]=[C:15]([CH3:21])[C:14]=1[CH2:22][CH2:23][S:24]([N:27]1[CH2:44][CH2:43][C:30]2([N:34]=[C:33]([CH:35]3[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]3)[NH:32][C:31]2=[O:42])[CH2:29][CH2:28]1)(=[O:26])=[O:25]>CC(C)=O>[C:1]([NH:9][C:10](=[S:11])[N:19]([C:17]1[CH:18]=[C:13]([CH3:12])[C:14]([CH2:22][CH2:23][S:24]([N:27]2[CH2:28][CH2:29][C:30]3([N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[NH:32][C:31]3=[O:42])[CH2:43][CH2:44]2)(=[O:26])=[O:25])=[C:15]([CH3:21])[CH:16]=1)[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CNc1cc(C)c(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCC(C)CC2)NC3=O)c(C)c1
Solvent: CC(C)=O
Product: Cc1cc(N(C)C(=S)NC(=O)c2ccccc2)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Yield: 104.5 %

Procedure:
Benzoyl isothiocyanate (37.8 mg, 0.23 mmol) was added to a solution of 8-[2-(2,6-dimethyl-4-methylamino-phenyl)-ethanesulfonyl]-2-(4-methyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (100 mg, 0.21 mmol) in acetone (3 ml) in a nitrogen stream. The mixture was heated under reflux for one hour and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 3-benzoyl-1-(3,5-dimethyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-1-methyl-thiourea (140 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:24][CH2:25]O>>[CH2:24]([O:16][C:15](=[O:17])[C@H:14]([OH:18])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:25]
Reactant: O=C(NCC[C@@H](O)C(=O)O)OCc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](O)CCNC(=O)OCc1ccccc1
Yield: 81 %

Procedure:
A solution of (R)-4-benzyloxycarbonylamino-2-hydroxy-butyric acid (2.42 g, 9.56 mmol) and sulfuric acid (94 mg, 0.96 mmol) in EtOH (6 mL) was heated at reflux for 18 h, then partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (2.18 g, 81%). Light yellow liquid, MS: 304.2 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[C@H:17]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH2:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:18][CH:19]=[CH:20][O:21]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(OC1OC=CN=C1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 159.3 %

Procedure:
A solution of (2R-cis)-2-[[1-[3.5-bis(trifluoromethyl)phenyl]-ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)mopholine (1082 g, 94% pure, 1.94 moles) in 1:1 ethyl acetate:ethanol (13 L) was mixed with 10% palladium-on-carbon (165 g). The resulting slurry was treated with hydrogen (40 psi, 20-25° C.) for 12 hours. The reaction was monitored by hydrogen uptake and HPLC. The vessel was vented, and the catalyst was removed by filtration. After washing the catalyst with 1:1 ethyl acetate:ethanol (6 L) followed by ethyl acetate (2 L), the combined organic phases containing crude product were vacuum concentrated. A second batch, starting with 1078 g of (2R-cis)-2-[[1-[3.5-bis(trifluoromethyl)phenyl]ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)mopholine (1.93 moles) was prepared. The resulting crude product was vacuum concentrated and combined with the first batch. The combined batches of crude product were flushed with methyl-t-butyl ether (2×3 L) in order to remove residual ethyl acetate and ethanol, then were dissolved in methyl-t-butyl ether (3 L). The solution was assayed to contain 1348 g (3.09 moles, 80% yield) of the title compound (as the free base). Alternatively, 60 g of the vinyl ether, 650 mL of methyl t-butyl ether (MTBE), and 18 g of 5% Pd on alumina were stirred under 40 psi hydrogen pressure at 40° for 12 H. Assay yield was 87%, with a 91:9 ratio of diastereomers. At the end of the reaction age, the catalyst was removed by filtration through Solka-Floc, then the filtrate was concentrated to 140 mL.
Reaction SMILES: [F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]2([CH3:20])[CH3:19])[C:3]([O:5]C)=[O:4].O.[OH-].[Na+]>CO>[F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])([CH3:18])[CH2:12][CH2:11][C:10]2([CH3:20])[CH3:19])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(F)(F)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)O)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Methyl 2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetate 15 (1.38 g, 4.65 mmol) was dissolved in methanol (129 mL). Water (12.9 mL) and NaOH (1.04 g, 18.57 mmol) were successively added at RT. The mixture was stirred at 70° C. for 1 h. The mixture was evaporated in vacuo. The crude product was dissolved in water and extracted with diethyl ether (2×50 mL). The aqueous layer was acidified by HCl (1M) to about pH=1 and extracted with diethyl ether (3×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to obtain 2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetic acid 16 (1.27 g, 96.5% yield) as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCC(=O)OC(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 10 mmol), tert-butyl bromoacetate (2.35 g, 12 mmol) and cesium carbonate (10.5 g, 30 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 2 g (63%) 5-tert-butoxycarbonylmethoxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:9][CH2:10][N:11]([C:14]([NH:16][C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27](=[O:28])[NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)=[CH:30][CH:31]=3)=[CH:19][CH:18]=2)=[O:15])[CH2:12][CH2:13]1
Reactant: Nc1nccs1
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)N3CCC(=Cc4ccccn4)CC3)cn2)cc1
Product: O=C(Nc1nccs1)c1ccc(-c2ccc(NC(=O)N3CCC(=Cc4ccccn4)CC3)cn2)cc1
Yield: 47 %

Procedure:
Following the procedure of Example 13, using the compound obtained in Example 28 in place of 2-(4-(pyridin-2-ylmethylene)piperidine-1-carboxamido)thiazole-5-carboxylic acid and using 2-aminothiazole (30 mg, 290 μmol) in place of morpholine, the title compound (45 mg, 47%) was obtained as a white solid.