Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].C(C(C1C=CC=CC=1)(CCCC(OCC1C=CC=CC=1)CCCCC)CCCCCCC(OCC)=O)(=O)C>>[C:1]([C:4]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1)OCc1ccccc1
Product: CCCCCC(C)=CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1

Procedure:
By following the hydrolytic procedure of Example 3, Step E, but substituting ethyl 8-acetyl-8-phenyl-12-methyl-11-heptadecenoate for the ethyl 8-acetyl-8-phenyl-12-benzyloxyheptadecanoate therein employed there is obtained 8-acetyl-8-phenyl-12-methyl-11-heptadecenoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:27]=1.C(N(CC)CC)C>CS(C)=O.O>[Br:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[N:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)cc(C=C3CCNCC3)c2)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Reaction time: 8 h
Yield: 66 %

Procedure:
2-(3-Bromo-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (0.57 g, 1.379 mmol) and phenyl pyridazin-3-ylcarbamate (0.296 g, 1.38 mmol) were dissolved in DMSO (4 mL). Triethylamine (0.57 mL, 4.13 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography (37% acetone in hexane) to give the title compound (0.486 g, 66%). 1H NMR (500 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.41 (dd, J=4.75 Hz, 1H), 7.24 (s, 1H), 7.20 (s, 1H), 7.04 (d, J=9 Hz, 1H), 6.94 (s, 1H), 6.35 (s, 1H), 3.69 (m, 2H), 3.60 (m, 2H), 2.58 (m, 2H), 2.17 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 165.16, 156.80, 153.50, 145.43, 140.30, 139.57, 136.97, 128.86, 128.09, 124.66, 123.35, 122.86, 122.49, 122.24, 121.98, 120.73, 111.67, 45.55, 44.52, 35.74, 29.29, 29.18; m/z (534.1, 536.1, M+ H+); HPLC: 99.0%.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C@H:8]([NH:11][S:12]([C:15]2[CH:23]=[CH:22][C:18]3[N:19]=[CH:20][S:21][C:17]=3[CH:16]=2)(=[O:14])=[O:13])[CH2:9][OH:10])=[CH:5][CH:4]=1)=[O:2].N1C=CN=C1.[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[Si:33]([O:10][CH2:9][C@@H:8]([NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][S:21][C:17]=2[CH:16]=1)(=[O:14])=[O:13])[C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)([C:30]([CH3:32])([CH3:31])[CH3:29])([CH3:35])[CH3:34]
Reactant: O=Cc1ccc([C@@H](CO)NS(=O)(=O)c2ccc3ncsc3c2)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](NS(=O)(=O)c1ccc2ncsc2c1)c1ccc(C=O)s1
Reaction time: 8 h

Procedure:
To a solution of N-[(1R)-1-(5-formylthiophen-2-yl)-2-hydroxyethyl]-1,3-benzothiazole-6-sulfonamide (5.48 g, 14.9 mmol) and imidazole (1.27 g, 18.6 mmol) in DMF (75 mL) was added TBSCl (2.80 g, 18.6 mmol) and the reaction mixture was stirred overnight. The reaction was then quenched by the addition of water (400 mL) and ether (200 mL). The phases were separated and the aqueous layer was extracted with ether (3×250 mL). The combined organic layers were washed twice with brine solution (2×300 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.[C:16](Cl)(=[O:18])[CH3:17]>>[C:16]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)(=[O:18])[CH3:17].[CH:16]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)=[O:18]
Reactant: CC(=O)Cl
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Product: CC(=O)OC1(C)CCCC(C)(C)C12CCC(C)O2
Product: CC1CCC2(O1)C(C)(C)CCCC2(C)OC=O

Procedure:
2,6,10,10-Tetramethyl-1-oxa-spiro[4.5]dec-6-yl acetate was prepared as indicated hereinabove, from 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol and acetyl chloride. 2,6,10,10-Tetramethyl-1-oxa-spiro[4.5]dec-6-yl formate on the contrary was obtained by treating the above alcohol with formylimidazole, according to the method given in Liebigs Ann. Chem. 655, 95 (1962).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@:10](/[CH:26]=[C:27](/[C:29]1[CH:34]=[C:33]([O:35][C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:31][C:30]=1[O:40][CH:41]1[CH2:43][CH2:42]1)\I)([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[O:89]1CCC[CH2:90]1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C@H:13]2[CH2:12][CH2:11][C@@:10]3([CH:26]=[C:27]([C:29]4[CH:34]=[C:33]([O:35][C:36]([F:38])([F:39])[F:37])[CH:32]=[CH:31][C:30]=4[O:40][CH:41]4[CH2:42][CH2:43]4)[C:90](=[O:89])[O:25]3)[C@:9]1([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:15][C@H:14]2[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(O)/C=C(\I)c1cc(OC(F)(F)F)ccc1OC1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1O[C@@]2(C=C1c1cc(OC(F)(F)F)ccc1OC1CC1)CC[C@H]1[C@H](S(=O)(=O)c3ccccc3)C[C@]2(c2ccccc2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-[(Z)-2-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-2-iodoethenyl]-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 690 mg, 0.86 mmol), 1,4-bis(diphenylphosphino)butane (45 mg, 0.1 mmol), Pd2(dba)3 (140 mg, 1.5 mmol), ethyl di-iso-propyl amine (0.75 ml) and tetrahydrofuran (20 ml) was stirred under an atmosphere of carbon monoxide (1 atm) at +50° C. for 24 hours. Additional portion of 1,4-bis(diphenylphosphino)butane (45 mg, 0.1 mmol) and Pd2(dba)3 (140 mg, 1.5 mmol) were added and the mixture was stirred for an additional 24 hours. After cooling to room temperature the mixture was diluted with ethyl acetate and filtered through a pad of Celite™. The filtrate was concentrated and the residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-35%) to give the title compound (350 mg, 58%).
Reaction SMILES: [NH3:1].F[C:3]1[C:10]([F:11])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N:12](S(C)(=O)=O)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:4]=1>O1CCCC1>[NH2:1][C:3]1[C:10]([F:11])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:4]=1
Reactant: N
Reactant: CS(=O)(=O)N(c1cc(F)c(F)cc1C#N)S(C)(=O)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(N)c(F)cc1C#N
Temperature: 150 °C
Yield: 34 %

Procedure:
In a 100 ml autoclave, 2 ml of ammonia are condensed and 2.0 g (6.4 mmol) of 4,5-difluoro-2-(bis-methanesulphonyl-amino)-benzonitrile and 40 ml of tetrahydrofuran are added. The reaction mixture is then heated in the closed autoclave at 150° C. for 15 hours. After cooling, the mixture is filtered and the filtrate is concentrated under water pump vacuum. Washing with 2N hydrochloric acid and with water gives 0.50 g (34% of theory) of N-(5-amino-2-cyano-4-fluoro-phenyl)-methanesulphonamide of melting point 235° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([CH2:50][CH3:51])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][CH2:50][CH3:51])=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: CCN=C=O
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 25 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 25% yield. LCMS for C27H31ClN7O2 (M+H)+: m/z=520.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1.[CH3:45][S:46](Cl)(=[O:48])=[O:47].CCOC(C)=O>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][S:46]([CH3:45])(=[O:48])=[O:47])[N:8]=2)[C:21]=1[F:38])(=[O:28])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Yield: 33.3 %

Procedure:
To a suspension of N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) in dichloromethane (0.500 ml) was added pyridine (0.036 ml, 0.444 mmol) and a solution of methane sulphonyl chloride (0.025 g, 0.222 mmol) in dichloromethane (0.2 ml) and stirred overnight. The reaction was concentrated. The crude product was added to a silica gel column and eluted with DCM with MeOH (0% to 10%) and collected fractions to obtain crude product. The crude product was treated with EtOAc and hexanes and sonicated to form a white solid. The solid was filtered to obtain 2,5-difluoro-N-{2-fluoro-3-[5-(2-{[(methylsulfonyl)amino]methyl}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide (38 mg, 33%) as white solid. MS (ESI): 641 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]=2)[CH:5]=[C:4]([C:16](O)=[O:17])[C:3]1=[O:19].C(Cl)(=O)C([Cl:23])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]=2)[CH:5]=[C:4]([C:16]([Cl:23])=[O:17])[C:3]1=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)c(C(=O)O)cc2ccc(C(F)(F)F)nc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C(=O)Cl)cc2ccc(C(F)(F)F)nc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
0.83 g (3.0 mmol) of 1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 1.0 mL (12 mmol) of oxalyl chloride was added thereto. Two droplets of N,N-dimethylformamide were added to the above mixture, and the resulting mixture was stirred for 2 hours at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in acetonitrile (30 mL), and this solution was added to an acetonitrile (50 mL) solution of 0.38 g (3.4 mmol) of 1,3-cyclohexanedione and 0.51 mL (3.7 mmol) of triethylamine under ice cooling. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and was dried and concentrated. The residue was washed with diisopropyl ether, and thus 0.51 g (yield: 46%) of the title compound was obtained as brown crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[CH2:15][C:14](=[O:16])[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:20][CH:21](OCC)OCC)(=O)[CH3:18]>>[CH2:17]([O:20][CH:21]=[C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:13][C:14]1=[O:16])[CH3:18]
Reactant: CCOC(OCC)OC(C)=O
Reactant: O=C1Cc2cc(-c3ccccc3)cnc2N1
Product: CCOC=C1C(=O)Nc2ncc(-c3ccccc3)cc21

Procedure:
This compound was synthesized from 5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ10.93 (s, 1H); 8.24 (s, 1H); 7.86-7.82 (m, 2H); 7.62-7.56 (m, 2H); 7.44 (m, 2H); 7.34 (m, 1H); 4.40 (m, 2H); 1.35 (m, 3H).
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][PH:8](=[O:13])[O:9]C(C)C)[CH2:3]1.CCOC(/[N:19]=N/C(OCC)=O)=O.N=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C1COCC1.O>[NH2:19][C@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][PH:8](=[O:13])[OH:9])[CH2:3]1
Reactant: CC(C)O[PH](=O)C[C@H]1CC[C@@H](O)C1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: [N-]=[N+]=N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O
Product: N[C@H]1CC[C@H](C[PH](=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.4 %

Procedure:
To a stirred solution of (±)-cis-isopropyl (3-hydroxycyclopentanyl)methylphosphinate (6) (1.6 g, 7.8 mmol), DEAD (2.5 cm3, 17.05 mmol) and HN3 (8.2 cm3 of a 1.9 M solution in benzene) in anhydrous THF (70 cm3) under an atmosphere of N2 at 0° C. was added triphenylphosphine (8.15 g, 31.2 mmol) in small portions over a period of 1 h. The reaction mixture was allowed to warm to room temperature and stirring continued for 12 h. The reaction mixture was then heated to 50° C. for 3 h after which time water (2 cm3) was added and heating continued for a further 2 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between aqueous HCl (1 M, 30 cm3) and DCM (30 cm3). The organic layer was separated and further extracted with aqueous HCl (2×30 cm3). The combined aqueous fractions were washed with DCM (2×30 cm3) and concentrated in vacuo. The crude amino ester hydrochloride salt was hydrolysed by refluxing in aqueous HCl (6M) for 30 h after which time the reaction mixture was cooled to room temperature and the aqueous HCl removed under reduced pressure. The crude product was purified by ion exchange chromatography (Dowex 50, H+), eluting first with water until the eluate was colourless and pH 7. On further elution with aqueous pyridine (1M), ninhydrin positive fractions were collected and the solvent removed in vacuo giving an off white foam. Recrystallisation from ethanol/acetone followed by drying gave the desired product (7) (0.68 g, 43%): 1H NMR (300 MHz, D2O) δ 1.17 (3H, d, J=12.3 Hz, PCH3), 1.52-2.06 (7H, m, C(1)—H, C(2)—H, C(2)-—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′), 3.73 (1H, m, C(3)—H), 13C NMR (75.46 MHz, D2O) δ 13.16 (PCH3, d, JPC=91.6 Hz), 25.10 (C(5)), 31.31 (C(2)) 30.50 (C(4), d, 3JPC=11.4 Hz), 37.34 (C(1), d, JPC=98.2 Hz), 52.40 (C(3), d, 3JPC=9.7 Hz), 31P NMR (121 MHz, D2O) δ 45.9, MS (CI, CH4) m/z 164 (38%) (MH+), 147 (30), 105 (100), (ESI) 164.0821 (MH+-C6H15NO2P requires 164.0840).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Cl-].[CH3:8][O:9]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]3[CH2:50]CC(=O)C[CH2:46]3)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)[CH2:31][CH3:32].Cl>C1COCC1.O>[CH3:8][O:9][CH:1]=[C:2]1[CH2:5][CH2:50][CH:45]([CH:42]2[CH2:41][CH2:40][CH:39]([C:36]3[CH:37]=[CH:38][C:33]([CH2:30][CH2:31][CH3:32])=[CH:34][CH:35]=3)[CH2:44][CH2:43]2)[CH2:46][CH2:3]1
Reactant: CCCc1ccc(C2CCC(C3CCC(=O)CC3)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(C2CCC(C3CCC(=COC)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 55.0 g (0.50 mol) of potassium tert-butoxide in 250 ml of THF is added to a suspension of 170.0 g (0.50 mol) of methoxymethyltriphenylphosphonium chloride in 550 ml of THF at 0° C. After 30 min at this temperature, a solution of 4′-(4-propylphenyl)bicyclohexyl-4-one in 450 ml of THF is added, and the mixture is stirred at room temperature for 17 h. Water is added to the batch, which is then acidified using hydrochloric acid. The mixture is extracted a number of times with MTBE, and the combined organic phases are washed with water and saturated sodium chloride solution. The solution is concentrated to completion, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=8:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30](=[O:32])[CH3:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]([OH:32])[CH3:31])=[O:22])=[CH:34][CH:35]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C(C)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-acetylphenyl)benzamide (200 mg) in methanol (15 ml) was added sodium borohydride (16.4 mg) and the solution was stirred at ambient temperature for 3 hours. Chloroform was added to the mixture and the solution was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give a syrup and the crude product was purified by silica gel column (chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(1-hydroxyethyl)phenyl]-benzamide (150 mg) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>O1CCCC1>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([CH3:2])[CH:4]=2)=[O:29])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.8 %

Procedure:
3-Methyl-4-methanesulfonylaminobenzylamine hydrochloride (140 mg, 0.56 mmol), 3-(4-t-butylphenyl)acrylic acid (1.1 eq, 0.13 g), and DMTMM (1.1 eq, 0.185 g) were added into 25 ml tetrahydrofuran. The reaction mixture was stirred 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed 1N HCl solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=2/1) to yield a solid (49 mg).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10]3[O:12][C:37](=[O:38])[C:36]([S:35][CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:40]([OH:41])[CH:11]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc3c(c2)OCO3)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3',4'-(methylenedioxy)acetophenone (0.871 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio] propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ3.98 (s, 2 H), 6.13 (s, 2 H), 6.61 (s, 1 H), 7.05 (d, 2 H), 7.27 (m, 7 H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CO[CH2:24][CH2:25]O>>[CH3:10][C:9]1[NH:12][C:13]([N+:1]([O-:4])=[O:2])=[C:24]([CH3:25])[C:8]=1[C:7]1[CH:6]=[CH:11][N:15]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)[N:14]=1
Reactant: COCCO
Reactant: N=C(N)Nc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1[nH]c([N+](=O)[O-])c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: 120 °C

Procedure:
3-Dimethylamino-1-(2,4-dimethyl-5-nitro-1H-pyrrol-3-yl)-propenone (110 mg, 0.46 mmol), 4-fluorophenyl guanidine nitrate (150 mg, 0.7 mmol), and K2CO3 (193 mg, 1.4 mmol) were partially dissolved in 2-methoxyethanol and heated at 120° C. for 18 h. The mixture was concentrated in vacuo and purified by SiO2 chromatography (heptane/EtOAc gradient elution). The crude product was triturated in iPr2O to afford the title compound (22 mg) as a pale orange solid. M.p. 166.3–170.1° C. MS: [M+H]+=329.3 (C16H14FN5O2 requires 327.3). 1H-NMR (DMSO-d6) δ: 2.49 (s, 3H, CH3), 2.59 (s, 3H, CH3), 6.73 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.04 (t, 2H, J=8.8 Hz, Ph-H), 7.07 (br. s, 1H, NH), 7.55–7.58 (m, 2H, Ph-H), 8.44 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 9.40 (br. s, 1H, NH).
Reaction SMILES: [C:1](OCC)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>CCCCCC.ClCCl>[C:4]1([CH:3]=[CH:2][CH2:1][OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: OCC=Cc1ccccc1
Yield: 104.5 %

Procedure:
The above ester (3.52 g) was treated with diisobutylaluminium hydride (40 ml of a 1M solution in hexane) in dichloromethane (40 ml) in the normal fashion to provide 3-phenylprop-2-en-1-ol (2.8 g). NMR 1H: 7.2(5H,m), 6.55(1H,d), 6.35 (1H,t), 4.25(2H,d), 1.97(1H,s).