Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([OH:8])(=[O:7])[CH2:5][SH:6].Cl[CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CO>[C:4]([OH:8])(=[O:7])[CH2:5][S:6][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)CS
Reactant: CCCCCCC#CCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCC#CCC#CCSCC(=O)O
Reaction time: 0.5 h

Procedure:
3.85 ml of a 30% solution of sodium methoxide in methanol were added dropwise to a solution of 742 μl of thioglycolic acid in 8 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then a solution of 2 g of 1-chloro-2,5-dodecadiyne in 20 ml of methanol was added under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained crystallized at cold temperature. 3-Thia-5,8-pentadecadiynoic acid was recrystallized from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11]>>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](=[O:14])[O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:11]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)Oc1ccc(F)c(Cl)c1

Procedure:
3-Chloro-4-fluorophenol was acylated with diethylcarbamoyl chloride to produce 3-chloro-4-fluorophenyl diethylcarbamate, which was converted to 3-chloro-4-fluoro-2-iodophenyl diethylcarbamate via ortho-metalation followed by treatment with iodine. Basic hydrolysis provided 3-chloro-4-fluoro-2-iodophenol, which was coupled to (2-hydroxyphenyl)boronic acid under Suzuki conditions to give 6-chloro-5-fluorobiphenyl-2,2′-diol. Copper-mediated cyclization provided 4-fluorodibenzo[b,d]furan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[SH:23][CH2:24][C:25](O)=[O:26]>>[C:20]([C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:25](=[O:26])[CH2:24][SH:23])[CH:3]=1)=[O:22])([CH3:19])[CH3:18])#[N:21]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: O=C(O)CS
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)CS
Yield: 79.9 %

Procedure:
A solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (500 mg, 1.704 mmol) in mercaptoacetic acid (3 mL, 43.2 mmol) was stirred at 100° C. for 2 h. Quenched with water and extracted with EtOAc. Organic layer was washed with NaHCO3 solution, brine, dried and evaporated. Purification by chromatography (0-4% methanol in CH2Cl2) gave pure 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetamido)-4-methylphenyl)benzamide 16 (500 mg, 80%). 1H-NMR (400 MHz, CDCl3) 1.78 (s, 6H), 2.31 (s, 3H), 3.45 (d, J=9.4 Hz, 2H), 7.21 (d, J=8.2 Hz, 1H), 7.52 (t, J=8.2 Hz, 1H), 7.70-7.79 (m, 3H), 7.92-8.08 (m, 3H), 8.67 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.Cl[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH2:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[N:9]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(CS(=O)(=O)c3ccccc3)n2)CC1
Temperature: -10 °C
Yield: 85 %

Procedure:
A stirred solution of 1-methyl-4-(5-nitropyridin-2-yl)piperazine (1.10 g, 5.00 mmol) and chloromethylphenylsulfone (0.950 g, 5.00 mmol) in dry THF, under nitrogen, is cooled to −60° C., treated with 1.0 M KOtBu in THF (10.0 mL, 10.0 mmol), allowed to warm to −10° C. over a 1 h period, quenched with acetic acid, treated sequentially with water and saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from EtOAc to give the title compound as a yellow solid, 1.60 g (85% yield), mp: 170°-172° C., identified by mass spectral and NMR analyses.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:13][S:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:21]([OH:22])[C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: CS(=O)(=O)c1ccc(C(O)c2ccccc2C(F)(F)F)cc1
Yield: 108.6 %

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (14.5 mmol) and 4-(methylsulfonyl)benzaldehyde (2.68 g, 13.8 mmol) using the procedure described for compound (96). The product was obtained as an amber gum (4.95 g, 100%).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OCCN2CCOCC2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(OCCN2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-(2-(morpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoate (0.059 g) in methanol (2.0 mL) and ethyl acetate (2.0 mL), 10% palladium-carbon (0.012 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration. Trifluoroacetic acid (4.0 mL) was added to the obtained solid substance, followed by stirring at room temperature for 3 hours. Toluene was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration. Ethanol (4.0 mL) was added to the obtained solid substance. After adjusting the pH to 7.7 with a 1 mol/L aqueous solution of sodium hydroxide, the solid substance was collected by filtration to obtain 0.011 g of 2-(2-hydroxy-4-(2-(morpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccc(OC)cc2)c1

Procedure:
4-Methoxyphenylboronic acid (179 mg) and ethyl 2-chloroisonicotinate (200 mg) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:19]3[N:23]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[N:22]=[CH:21][CH:20]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:5]2=[CH:4][CH:3]=1.[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[Cl:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: Clc1cccc(Cn2c(-c3ccnn3C3CCCCO3)cc3nc(Cl)ccc32)c1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3ccnn3C3CCCCO3)n2Cc2cccc(Cl)c2)n1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
5-Chloro-1-(3-chlorobenzyl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[3,2-b]pyridine (0.87 g, 1.8 mmol, from Step 3), di-tert-butyl hydrazine-1,2-dicarboxylate (0.64 g, 2.7 mmol, Aldrich) and Cs2CO3 (0.90 g, 2.7 mmol, Aldrich) were combined in toluene (16 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.14 g, 0.18 mmol, Aldrich) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was heated in a sealed vial to 130° C. for 55 minutes, then at 135° C. for 40 minutes. Additional di-tert-butyl hydrazine-1,2-dicarboxylate (0.32 g, 1.4 mmol), Cs2CO3 (0.45 g, 1.4 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.10 g, 0.13 mmol) were added. The mixture was again degassed, then sealed and heated to 140° C. for 40 minutes. After cooling to room temperature, the mixture was diluted with DCM, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded product as a white solid (0.51 g, 40%). LCMS (M+H)+: 623.3.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9](C)[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:31])[C:23]=4[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CC(F)(F)C(=O)NC3C=NC(NC4C=CC(C(NC5CCN(C)CC5)=O)=C(F)C=4F)=NC2=3)CCCC1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:104][CH:105]1[CH2:110][CH2:109][N:108]([CH2:111][CH3:112])[CH2:107][CH2:106]1>CN(C)C=O.C(OCC)(=O)C.O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:104][CH:105]5[CH2:110][CH2:109][N:108]([CH2:111][CH3:112])[CH2:107][CH2:106]5)=[O:27])=[C:24]([F:31])[C:23]=4[F:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)c(F)c3F)ncc21
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4)c(F)c2F)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4)c(F)c2F)CC1
Reaction time: 0.25 h

Procedure:
A mixture of 0.0801 g of the 2:1 mixture of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,3-difluoro-benzoic acid and 4-{4-[(2-carboxy-2,2-difluoro-ethyl)-cyclopentyl-amino]-5-methylamino-pyrimidin-2-ylamino}-2,3-difluoro-benzoic acid (from example 243) in 7 mL of dimethylformamide was treated with 0.154 g (0.393 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.1185 g (0.918 mmole) of diisopropylethylamine. After 15 minutes, 0.0328 g (0.256 mmole) of 4-amino-1-ethylpiperidine in 1 mL of dimethylformamide was added. The reaction mixture stirred for 30 minutes and then diluted with 150 mL of ethyl acetate and 25 mL of water. The mixture was then washed successively with 20 mL of ammonium chloride, 20 mL of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0651 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-2,3-difluoro-benzamide (I-244) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[C:12]1([CH2:11][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)[CH:3]=2)[C:9]#[N:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC(Cc1ccccc1)c1cccc(Br)c1
Product: N#CC(Cc1ccccc1)c1cccc(-c2cn[nH]c2)c1

Procedure:
2-(3-Bromo-phenyl)-3-phenyl-propionitrile was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. (LC/MS: (PS-A) Rt 2.98 [M+H]+ 274).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N+:15]([O-])=O>CO.[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[NH2:15]
Reactant: COCOc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCOc1cc(C(F)(F)F)ccc1N
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of 2-nitro-5-trifluoromethylphenyl methoxymethyl ether (353 mg; prepared in Reference Example 19.) in MeOH (3.5 ml), 10% Pd—C (30 mg) was added in a stream of argon. The mixture was stirred vigorously at room temperature under hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under the reduced pressure to give the title compound (313 mg) having the following physical data.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[CH3:21][C:22]1[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:27]([C:25]2[S:26][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:28])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: Cc1ccc(C(=O)O)s1
Product: Cc1ccc(C(=O)NCC(=O)NC(c2cccc(F)c2)c2cccc(F)c2)s1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 5-methyl-thiophene-2-carboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8](=[O:11])[NH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[S:19]>CC(C)=O>[CH2:21]([O:20][P:18]([O:11][C:8]1[S:9][C:10]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[N:7]=1)([O:23][CH2:24][CH3:25])=[S:19])[CH3:22]
Reactant: O=C1CCCc2[nH]c(=O)sc21
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8.4 g of 7-oxo-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one, 10.5 g of potassium carbonate and 100 ml of acetone was refluxed for 1 hour and after addition of 14.5 g of O,O-diethyl chlorothiophosphate thereto, the mixture was refluxed for another hour. The mixture was stirred at room temperature for 24 hours and the mineral salts formed were filtered off. The filtrate was distilled to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 6 -4 cyclohexane-ethyl acetate mixture resulted in 3.5 g of 2-(diethoxythiophosphoryloxy)-4,5,6,7-tetrahydro-7-oxo-benzothiazole with a refractive index of nD20 = 1.555.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:8][CH2:7][CH2:6]2)=[O:2].[C:38](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([N:17]([CH3:38])[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=1)(=[O:20])=[O:19])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][CH2:7][CH2:6]2)=[O:2]
Reactant: O=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(CC(=O)NC1CCCc2cc(C=O)ccc21)c1ccccc1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Yield: 106.3 %

Procedure:
The aldehyde, N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (0.11 g), was stirred in dry DMF (5 mL) with sodium carbonate (0.2 g) and methyl iodide (0.2 mL) at RT for 3 days. Aqueous workup gave the crude product, N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-[methyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-3-phenyl-propionamide (0.12 g). MS: 545.1 (M+1). This aldehyde (0.12 g) was converted to 3-[methyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-3-phenyl-N-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamide using the general reductive amination conditions (amine, NaBH(OAc)3, RT, DCE) described earlier in this application. MS: 614.1 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)=[O:2].[OH-].[Na+].C1(C)C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:24][S:23][C:20]1[N:21]=[CH:22][C:11]2[C:10](=[O:25])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[O:2][CH:39]=[N:38][CH:37]=4)[CH:4]=3)[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]=2[N:19]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C=O)c1)C2=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3cnco3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
(S)-5-(3-Formylphenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (380 mg, 1.07 mmol) obtained in Step 2 was dissolved in methanol (10 mL), and the mixture was stirred at room temperature for 30 minutes after adding sodium hydroxide (120 mg, 2.14 mmol) and p-toluenesulfonylmethylisocyanide (230 mg, 1.18 mmol). After diluting the mixture with ethyl acetate, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(1,3-oxazol-5-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (300 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH:11]=O.[Cl-].[CH3:14][O:15]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH2:10][CH2:11][CH:14]=[O:15]
Reactant: CC1=C(CC=O)C(C)(C)CCC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC1=C(CCC=O)C(C)(C)CCC1
Yield: 80 %

Procedure:
2,6,6-Trimethyl-1-cyclohexene-1-acetaldehyde is reacted with methoxymethyl triphenylphosphonium chloride in the presence of potassium tert-butoxide, followed by conversion to the dimethyl acetal and subsequent hydrolysis, as described in Example 1 above, to provide 3-(2,6,6-trimethyl-1-cyclohexen-1yl)propanal (80% yield) as a colorless oil after distillation in vacuo. This material (6.8 g) is reacted with triethyl 2-phosphonopropionate (10.6 ml) by the method of example 14(B) above, to provide 6.58 g (2E)-2-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-pentenoic acid ethyl ester as a colorless oil after chromatography. This ester is reduced with diisobutylaluminum hydride by the method described in example 14(B) above, to provide (2E)-2-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-pentenol as a colorless oil (93%) after chromatography.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[OH:16][C:17]1[C:25]2[O:24][CH:23]=[C:22]([CH3:26])[C:21]=2[CH:20]=[C:19]([CH3:27])[C:18]=1[CH3:28]>ClCCCl>[OH:16][C:17]1[C:25]2[O:24][C:23]([C:1](=[O:10])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)=[C:22]([CH3:26])[C:21]=2[CH:20]=[C:19]([CH3:27])[C:18]=1[CH3:28]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc2c(C)coc2c(O)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2oc3c(O)c(C)c(C)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 189.3 %

Procedure:
To p-anisoyl chloride (205 g) in 1,2-dichloroethane (2 L), cooled to 0° C., was added AlCl3 (240 g). The reaction mixture was warmed to room temperature and a solution of 7-hydroxy-3,5,6-trimethylbenzofuran (51 g) in 1,2-dichloroethane (400 mL) was added dropwise. The reaction was stirred for 51/2 h then quenched with H2O (2 L). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were washed with 25% NH4OAc buffer, dried (Na2SO4) and filtered on silica gel to give 170 g of crude material which was used as such in the next step.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]([NH:20][C:21]1[CH:22]=[C:23]([NH:27][CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=1)(=[O:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50]([O:30][C:29](=[O:31])[CH:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:17](=[O:19])[CH3:18])[CH:22]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:49]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(=O)Nc1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
PS-DCC (798 mg, 0.10 mmol, loading: 1.25 mmol/g) is suspended in dry THF (10 mL). (3-Acetylamino-phenylamino)-phenyl-acetic acid hydrochloride (I45) (160 mg, 0.50 mmol), HOBT (153 mg, 0.10 mmol), and (R)-quinuclidin-3-ol (190 mg, 1.50 mmol) are added and the mixture is shaken for 16 hours at RT (Conversion complete by UPLC/MS-UV). PS-DCC is filtered off and washed with THF and then with EtOAc. The filtrate is evaporated, the resulting residue is taken up with EtOAc and washed with 5% NaHCO3, water and brine. The organic layer is separated, dried over Na2SO4, filtered and evaporated to afford the title compound as a yellow oil (196 mg, quantitative yield, mixture of diastereoisomers).