Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH:13]1[N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:17](=[O:23])[N:16]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:15]2[CH2:34][CH2:35][C:36](=[O:37])[C:14]1=2)[C:8]#[N:9])(=O)=O.O=C1N(C2C=CN=C(C(F)(F)F)C=2)C2CCC(=O)C=2C(C2C=CC(C#N)=CC=2)N1>>[CH3:22][S:19]([N:18]1[CH:13]([C:12]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[C:14]2[C:36](=[O:37])[CH2:35][CH2:34][C:15]=2[N:16]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[C:17]1=[O:23])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2ccnc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Agent: N#Cc1ccc(C2NC(=O)N(c3ccnc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Product: CS(=O)(=O)N1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1

Procedure:
The title compound is prepared in analogy to 3-(methylsulfonyl)-4-(3-(methylsulfonyl)-2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 39), using 4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4, 5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 15.5, 60 mg, 0.15 mmol) as starting material. Yield: 30 mg; ESI mass spectrum [M+H]+=477; Retention time HPLC: 0.99 min (Z018_S04).
Reaction SMILES: CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[NH2:18][C:19]1[CH:20]=[N:21][N:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:23]=1.CCN(CC)CC>CC(O)(C)C.ClCCCl.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[CH:23]=2)[N:12]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Reaction time: 0.17 h

Procedure:
A 1.0 M solution of ZnCl2 in Et2O (22.5 mL, 22.5 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (4.48 g, 20.7 mmol) in t-BuOH (50 mL) and DCE (50 mL) and the mixture was stirred for 10 minutes. The mixture was diluted with t-BuOH (50 mL) and DCE (50 mL) before tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (5.00 g, 18.8 mmol) and Et3N (3.14 mL, 22.5 mmol) were added. Stirring was continued overnight and the volatiles were subsequently removed in vacuo. The resultant residue was suspended in acetone (50 mL) then water (500 mL) and sonicated for 15 minutes before the solid was removed by vacuum filtration and the filter cake washed with water (100 mL). The solid was suspended in acetone (25 mL), filtered and the filter cake was washed with petroleum benzine 40-60° C. (200 mL) to give the title compound K8 as a light pink solid (6.57 g, 78%). LCMS-D: rt 3.618 min; m/z 445.1 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[F:26])(O)O>>[F:26][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:17]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[CH:3]=1)[C:21]([OH:23])=[O:22]
Reactant: Oc1ccc2cc(Br)ccc2c1F
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Product: O=C(O)c1ccc(-c2ccc3c(F)c(O)ccc3c2)c(F)c1

Procedure:
Followed the coupling procedure described in Example 29 starting from 6-bromo-1-fluoronaphthalen-2-ol (Intermediate 13) and 4-borono-3-fluorobenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.32 (b, 1H), 10.28 (b, 1H), 8.14 (s, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.73-7.76 (m, 4H), 7.32 (t, 1H), MS (ESI): m/z=299.40 [M−1]−.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][C:50]([OH:52])=O)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:50](=[O:52])[CH2:49][CH:46]1[CH2:45][CH2:44][N:43]([C:41]([O:40][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:42])[CH2:48][CH2:47]1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
N-methoxymethanamine hydrochloride (2.61 g, 26.7 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.91 g, 30.8 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (4.72 g, 30.8 mmol), and triethylamine (11.5 mL, 82.2 mmol) were added sequentially to a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (5.00 g, 20.6 mmol) in methylene chloride (150 mL) at 0° C. Stirred at ambient temperature for 4 hours, and partitioned between ethyl acetate and 2N HCl. Washed the organic layer again with 2N HCl, twice with 2N NaOH, brine, dried, and concentrated to afford the title compound (5.93 g, 101% yield) as a clear colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:13])[NH:5][C:6]2=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:24][CH:23]=1>CN(C=O)C>[CH:36]1([CH:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][N:5]3[C:4](=[O:13])[C:3]4[C:7](=[C:8]([F:11])[CH:9]=[CH:10][C:2]=4[F:1])[C:6]3=[O:12])=[CH:23][CH:24]=2)[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=C1NC(=O)c2c(F)ccc(F)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3c(F)ccc(F)c3C2=O)cc1)C1CCCC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
500 mg (2.71 mmol) of 4,7-difluoro-1H-isoindole-1,3(2H)-dione and 889.7 mg (2.71 mmol) of cesium carbonate were added to a solution of 964.7 mg (2.71 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate in 2 ml of DMF. The mixture was stirred at 60° C. for 2 h, and the reaction mixture was then added to ice-water. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 5:1). This gave 424 mg (34.1% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])=[CH:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.O1CCCC1>[C].[Pd].C(O)C>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:19]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCOc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
Catalytic hydrogenation of a mixture of ethyl(E)-3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propenoate (1.32 g), 5% palladium-carbon (1.0 g), tetrahydrofuran (40 ml) and ethanol (40 ml) was conducted at ordinary temperature and ordinary pressure. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in a mixed solution of tetrahydrofuran (10 ml) and ethanol (10 ml), then 1N aqueous sodium hydroxide solution (10 ml) was added to the solution, which was stirred at room temperature for 2 hours. The reaction mixture was poured into water, then neutralized with 1N hydrochloric acid (10 ml), which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (900 mg, yield: 72%). This was recrystallized from acetone-ethyl acetate. Melting point: 110–111° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1.[H-].[Na+].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C1COCC1>[C:30]([Si:27]([O:23][C:21]([CH3:24])([CH3:22])[CH2:20][C:11]1[CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:8]([C:9]=2[CH:10]=1)=[CH:7][C:6]([O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)=[CH:19][CH:18]=3)([CH3:29])[CH3:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(O)Cc1ccc2ccc3ccc(OCC4CC4)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(Cc1ccc2ccc3ccc(OCC4CC4)cc3c2c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of crude 1-[6-(cyclopropylmethoxy)-3-phenanthryl]-2-methylpropan-2-ol from Step 4 above in THF (10 mL), was added sodium hydride (60% dispersion in oil, 0.27 g, 6.79 mmol). The mixture was heated at reflux for 2 minutes, then cooled to room temperature. Tert-butyldimethylsilylchloride (0.512 g, 3.39 mmol) was added and the reaction mixture heated at reflux for 2 h. After usual workup of the reaction, tert-butyl(2-[6-(cyclopropylmethoxy)-3-phenanthryl]-1,1-dimethylethoxy)dimethylsilane (0.5 g) was obtained, which was used as crude material for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][C@@H:6]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH2:5][C@@H:4]([CH2:15]S(C2N(C3C=CC=CC=3)N=NN=2)(=O)=O)[O:3]1.[CH:31]1([C:34]2[C:43]([CH:44]=O)=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:31]1([C:34]2[C:43](/[CH:44]=[CH:15]/[C@H:4]3[O:3][C:2]([CH3:1])([CH3:30])[O:7][C@@H:6]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH2:5]3)=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:32][CH2:33]1
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](CS(=O)(=O)c2nnnn2-c2ccccc2)OC(C)(C)O1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CON(C)C(=O)C[C@H]1C[C@@H](/C=C/c2c(C3CC3)nc3ccccc3c2-c2ccc(F)cc2)OC(C)(C)O1
Temperature: -70 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
2-[(4R,6S)-2,2-dimethyl-6-(1-phenyl-1H-tetrazole-5-sulfonylmethyl)-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (16.6 g), 2-cyclopropyl-3-formyl-4-(4-fluorophenyl)quinoline (10.0 g), and tetrahydrofuran (400.0 mL) were added to a reactor and then the reaction mixture was cooled to −70° C. A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 36.0 mL) was slowly added to the reaction mixture, the temperature of which was adjusted to −20˜−10° C. The reaction mixture was stirred at the same temperature for 1 hour and then 8% sodium bicarbonate solution (80.0 mL) was added thereto under stirring. The separated organic layer was washed with water (60.0 mL) and then concentrated under reduced pressure to obtain E-(6-{2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide as a solid (15.6 g, yield 90%).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[C:7]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:8][C:9]2[C:10]3[N:11]([C:17](=[O:20])[NH:18][N:19]=3)[C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1)([O-:5])=[O:4]>CN(C)C=O>[N+:3]([C:6]1[C:7]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:8][C:9]2[C:10]3[N:19]([NH:18][C:17](=[O:20])[N:11]=3)[C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1)([O-:5])=[O:4]
Reactant: O=c1[nH]nc2c3cc(N4CCCC4)c([N+](=O)[O-])cc3[nH]c(=O)n12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1nc2c3cc(N4CCCC4)c([N+](=O)[O-])cc3[nH]c(=O)n2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
9.86 ml of 0.1M NaOH were added to a solution of 200 mg (0.63 mmol) of 8-nitro-9-pyrrolidin-1-yl-2,3,5,6-tetrahydro[1,2,4]triazolo[4,3-c]quinazoline-3,5-dione and 20 ml of dimethylformamide and the mixture was stirred at room temperature for 30 min. Subsequently, the mixture was concentrated to dryness, treated 3 times with deionized water and again concentrated. The residue was dried in a high vacuum. There were obtained 193 mg (90%) of 8-nitro-9-pyrrolidin-1-yl-2,3,5,6-tetrahydro-[1,2,4]triazolo[1,5-c]quinazoline-2,5-dione as a red-brown powder.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[NH2:29]>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:29][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([Br:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 95 %

Procedure:
The title compound (61 mg, 95%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid and (S)-3,4-dichlorophenylalanine methyl ester hydrochloride as in Example 1, Part C. 1H NMR (400 MHz, CDCl3): 11.43 (br s, 1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.90 (t, J=1.0, 1H), 7.73 (dd, J=8.8, 7.0, 1H), 7.35 (d, J=8.2, 1H), 7.14 (d, J=2.0, 1H), 7.11 (d, J=1.0, 2H), 6.89 (dd, J=8.2, 2.1, 1H), 6.48 (br d, J=7.1, 1H), 5.00-4.92 (m, 1H), 3.82 (s, 3H), 3.22 (dd, J=14.0, 5.8, 1H), 3.16 (dd, J=14.0, 5.1, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:17]2[CH2:16][O:15][C:14]([CH3:19])([CH3:18])[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1>CN(C=O)C>[CH3:18][C:14]1([CH3:19])[O:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][CH2:6][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:17]=2[CH2:16][O:15]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC1(C)OCc2c(CCOS(C)(=O)=O)cccc2O1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCc2cccc3c2COC(C)(C)O3)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl methanesulfonate (176 mg, 0.59 mmol, crude above, 1 eq.) in DMF (1.0 mL) was added ethyl piperidine-4-carboxylate (186 mg, 1.18 mmol, 2.0 eq.) at rt. The mixture was stirred at 60° C. for 2 h, cooled to rt, and purified on RP-HPLC (Gemini 21.2 mm×150 mm) using a mixture of CH3CN and water (0.1% HCOOH) as eluent to give ethyl 1-(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl)piperidine-4-carboxylate (100 mg, 49% for two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.73 (d, J=7.9 Hz, 2H), 4.86 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.22 (s, 2H), 3.09-2.95 (m, 1H), 2.95-2.79 (m, 4H), 2.76 (s, 1H), 2.66-2.48 (m, 1H), 2.23-1.99 (m, 4H), 1.55 (s, 6H), 1.29 (t, J=7.1 Hz, 3H). LRMS (M+H+) m/z 348.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])OCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:26][C@H:27]([C:29]([N:31]([CH3:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:30])[CH3:28].C(N(CC)CC)C>O1CCCC1.C1C=CC=CC=1>[CH2:16]([O:15][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([NH:26][C@H:27]([C:29]([N:31]([CH3:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:30])[CH3:28])=[O:18])[CH3:17]
Reactant: CCOP(=O)(CCCCc1ccccc1)OCC
Reactant: CCOC(=O)CN(C)C(=O)[C@H](C)N
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CN(C)C(=O)[C@H](C)NP(=O)(CCCCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of (4-phenylbutyl)phosphonic acid, diethyl ester (0.97 g., 3.6 mmole), dry benzene (10 ml.), and phosphorus pentachloride (0.75 g., 3.6 mmole) is refluxed under argon for 20 minutes. The phosphorus oxychloride and benzene are removed in vacuo, and the residue is taken up in dry tetrahydrofuran (10 ml.) and treated with N-(L-alanyl)-N-methylglycine, ethyl ester, hydrochloride (0.67 g., 3.0 mmole). The resulting suspension is cooled to 0° (ice-bath) and treated dropwise with triethylamine (1.2 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over a period of 2 minutes in an argon atmosphere. After stirring at 0° for 20 minutes the ice bath is removed and the reaction mixture is stirred for an additional 4 hours. The reaction mixture is then diluted with ethyl acetate and washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, brine, dried (MgSO4), and evaporated. The residue (1.4 g.) is chromatographed on silica gel (60 g.) eluting with toluene/acetone (1:1) to give 1.0 g. of N-[N-[ethoxy(4-phenylbutyl)phosphinyl]-L-alanyl]-N-methylglycine, ethyl ester as an oil after evaporation. Tlc (toluene/acetone; 1:1) shows a single spot at Rf =0.19.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2]
Reactant: CCCc1ccc(-c2ccc(C#Cc3ccc(OCC)c(F)c3F)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(CCc3ccc(OCC)c(F)c3F)cc2)cc1

Procedure:
0.031 mol of this ethine-derivative and 3 g of Pd-C (5%) are suspended in 100 ml of THF and hydrogenated at room-temperature under a hydrogen pressure of 1 bar. Customary working up gives 1-(4-ethoxy-2,3-difluorophenyl)-2-(4'-propylbiphenyl-4-yl)-ethane.
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH:36][CH:37]([CH2:42][NH:43][CH3:44])[C:38]([O:40]C)=[O:39].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:43]([CH3:44])[CH2:42][CH:37]([OH:36])[C:38]([OH:40])=[O:39])=[O:31])=[CH:33][CH:34]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CNCC(O)C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CC(O)C(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A solution of 4-[(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]benzoic acid (141 mg), methyl 2-hydroxy-3-(methylamino)propanoate hydrochloride (61 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg), hydroxybenzotriazole monohydrate (55 mg) and triethylamine (50 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (107 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][N:30]3[CH:25]4[CH2:26][CH2:27][CH:28]3[CH2:29][CH:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24]4)[C:6]=2[CH:17]=1
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(F)cc21
Yield: 71 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.208 g, 0.6 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.56 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF27) (0.16 g, 58%). 1H NMR (CDCl3) δ 7.13 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.68-6.63 (m, 1H), 4.57 (q, J=14.8 Hz, J=40.0 Hz, 1H), 4.11-3.94 (m, 2H), 3.14-3.04 (m, 2H), 2.30 (dd, J=4.0 Hz, J=12.8 Hz, 1H), 2.20-2.09 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.82 (m, 3H), 1.71-1.52 (m, 3H), 1.40-1.34 (m, 2H), 1.32-1.19 (m, 8H), 0.89-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.6 Hz), 130.0 (d, J=10.8 Hz), 117.5 (d, J=9.3 Hz), 109.4 (d, J=23.4 Hz), 103.8 (d, J=28.9 Hz), 67.8, 61.0, 59.0, 58.2, 45.5, 38.4, 36.6, 36.5, 32.8, 31.8, 28.4, 28.4, 28.2, 27.2, 22.8, 7.0, 14.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Br:17])=[C:4]2[N:11]([OH:12])[C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:5]2=[N:6][C:7]=1[Br:8].[CH3:18][N:19]=[C:20]=[O:21].C(N(CC)CC)C>C(OCC)C>[CH3:18][NH:19][C:20]([O:12][N:11]1[C:4]2[C:5](=[N:6][C:7]([Br:8])=[C:2]([Cl:1])[C:3]=2[Br:17])[N:9]=[C:10]1[C:13]([F:14])([F:16])[F:15])=[O:21]
Reactant: On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNC(=O)On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21
Reaction time: 0.25 h

Procedure:
6-Chloro-5,7-dibromo-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (0.9 gram) was mixed with ether (15 milliliters) and methyl isocyanate (2 milliliters) and stirred for 15 minutes. Triethylamine (0.01 milliliter) was added, and the solution became homogenous. It was permitted to stand for 16 hours, diluted with 50 milliliters diethyl ether; washed with 0.5N HCl, water, and saturated NaCl; then dried over magnesium sulfate, and evaporated. The resulting 1-(methylcarbamoyloxy)-6-chloro-5,7-dibromo-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product was recrystallized from chloroform, m.p. 216°C.