Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH:5]([C:16]([OH:18])=[O:17])[S:6][CH2:7][C:8](O)([CH3:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O=S(Cl)Cl.N1CCCCC1>C(Cl)(Cl)Cl>[CH2:9]([C:8]1([CH3:14])[O:17][C:16](=[O:18])[CH:5]([CH2:4][C:3]([OH:2])=[O:19])[S:6][CH2:7]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(C)(O)CSC(CC(=O)OC)C(=O)O
Solvent: C1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1

Procedure:
2.7 g of 6-hydroxy-3-hydroxycarbonyl-6-methyl-4-thiaundecanoic acid methyl ester and 1.25 g of SOCl2 are stirred for 2 hours in 40 ml of chloroform at room temperature. The mixture is boiled briefly. After cooling, 0.5 ml of piperidine, dissolved in 20 ml of chloroform is added thereto. The resultant mixture is further stirred for 1 hour at 30°. After the usual working up, 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid is obtained.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:11]2([CH3:27])[C@H:12]([O:22][C:23]([CH2:25][OH:26])=[O:24])[CH2:13][C@:14]([CH:20]=[CH2:21])([CH3:19])[C@@H:15]([OH:18])[C@H:16]([CH3:17])[C@:5]3([C@@H:10]2[C:8](=[O:9])[CH2:7][CH2:6]3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>CC(CC(C)C)=O.CCCCCCC>[CH3:1][C@H:2]1[C@:11]2([CH3:27])[C@@H:12]([O:22][C:23]([CH2:25][O:26][S:36]([CH3:35])(=[O:38])=[O:37])=[O:24])[CH2:13][C@@:14]([CH:20]=[CH2:21])([CH3:19])[C@H:15]([OH:18])[C@@H:16]([CH3:17])[C@@:5]3([C@@H:10]2[C:8](=[O:9])[CH2:7][CH2:6]3)[CH2:4][CH2:3]1
Reactant: C=C[C@]1(C)C[C@@H](OC(=O)CO)[C@]2(C)[C@H](C)CC[C@]3(CCC(=O)[C@@H]32)[C@@H](C)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: C=C[C@@]1(C)C[C@H](OC(=O)COS(C)(=O)=O)[C@@]2(C)[C@H](C)CC[C@@]3(CCC(=O)[C@@H]32)[C@H](C)[C@H]1O
Temperature: 21 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Pleuromutilin (20.1g) and triethylamine (6.86 g) in methylisobutyl ketone (0.21 L) were cooled to −10° C. Methane sulphonyl chloride (7.91 g) in methylisobutyl ketone (0.04 L) was added at −5 to −10° C. After 1 h water (0.12 L) was added and the mixture was warmed to 20-22° C. The phases were separated and the methylisobutyl ketone phase was washed successively with water (0.09 L) and 10% brine (0.05 L). The methylisobutyl ketone solution was concentrated by distillation under reduced pressure to leave a residue of 57.4g. Heptane (0.06 L) was added to the residue at 76-78° C. to crystallize the title compound. Further heptane (0.04 L) was added, the mixture was cooled to −5 to −8° C. and stirred for 1 h. The title compound was filtered off, washed with chilled heptane/methylisobutyl ketone (3:1, 0.028 L) and dried at <40° C. to give 21.94g, 90.5% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O:12][C:13](=O)[CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:15](=O)[CH3:16])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]2[C:2]=1[NH:1][C:15]([CH3:16])=[C:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:13]2=[O:12]
Reactant: Nc1cc(O)ccc1Cl
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1[nH]c2c(Cl)ccc(O)c2c(=O)c1Cc1ccc(Cl)cc1
Temperature: 160 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (2.5 g), 2-(4-chlorobenzyl)-3-oxobutyric acid ethyl ester (4.7 g) and toluene-4-sulfonic acid (0.3 g) was heated at 160° C. under nitrogen for 10 hours. The mixture was cooled to room temperature and the residue triturated with methanol and then crystallised from butan-1-ol to afford a beige powder. Purification by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 1:0 by volume) gave title compound as a yellow solid, 0.77 g.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([C:17]2([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[S:21][CH2:20][CH2:19][S:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[C:11]1([C:17]2([C:22]3[CH:23]=[CH:24][C:25]([C:26]([N:8]4[CH2:9][CH2:10][C:5]5[CH:4]=[CH:3][O:2][C:6]=5[CH2:7]4)=[O:27])=[CH:29][CH:30]=3)[S:21][CH2:20][CH2:19][S:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(C2(c3ccccc3)SCCS2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(C2(c3ccccc3)SCCS2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.582 g (9.912 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 3.00 g (9.91 mmol) of 4-(2-phenyl-1,3-dithiolan-2-yl)benzoic acid and 5.53 ml (39.6 mmol) of triethylamine in 50 ml of N,N-dimethylformamide, 1.80 ml (11.9 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 2/1) to yield the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Reactant: NOC1CCCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2)NOC1CCCCO1

Procedure:
(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (250 mg, 0.604 mmol) was reacted with NH2OTHP following the procedure described in Example 12, Step C, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (270 mg) as a light yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.C1COCC1.O.[Na+].[Cl-].C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:8][CH2:9][C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)C(=O)c1ccccc1
Yield: 94.2 %

Procedure:
(R)-tert-butyl 3-(tert-butyldimethylsilyloxy)-1-oxo-1-phenylpropan-2-ylcarbamate (23) (1.5 g, 4.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by a 1:1 mixture of THF/H2O (20 mL). The mixture was stirred and glacial acetic acid (30 mL) was added to the reaction flask. The reaction stirred for 22 h at rt. The reaction was transferred to a 500 mL separatory funnel with sat. NaCl (75 mL) and sat. NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (3×75 mL) and the combined organic layers were dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 1.3 g of crude material. The residue was purified by flash column chromatography (40% EtOAc/hexanes) to give 1.0 g (95%) of 24 as a colorless oil which crystallized to a white solid. Rf=0.27 (40% EtOAc/hexanes); mp=60-62° C.; [α]D23.5=+12.4 (c 1.01, MeOH); IR (KBr) 3420, 2976, 2931, 1683, 1503, 1366, 1165, 1061 cm−; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.5 Hz, 2H, Ph-H), 7.62 (t, J=7.5 Hz, 1H, Ph-H), 7.51 (t, J=7.5 Hz, 2H, Ph-H), 5.88 (br s, 1H, carbamate-NH), 5.35 (br s, 1H, Boc-NH—CH), 4.02 (m, 1H, CH—CH2), 3.86 (m, 1H, CH—CH2), 2.91 (br s, 1H, CH2—OH), 1.47 (s, 9H, t-butyl-CH3); 13C (125 MHz, CDCl3) δ 197.4, 156.3, 134.6, 134.1, 129.0, 128.9, 80.5, 64.7, 58.1, 28.4; LRMS (ESI-MS m/z): Mass calcd for C14H19NNaO4 [M+Na]+, 288.29. Found 288.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:4]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]2[N:30]=[CH:31][CH:32]=[CH:33][N:34]=2)=[C:24]([C:25]([N:13]2[CH2:14][CH:15]3[CH:11]([CH2:10][N:9]([C:5]4[N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=[CH:7][N:6]=4)[CH2:16]3)[CH2:12]2)=[O:26])[CH:28]=1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: FC(F)(F)c1ccnc(N2CC3CNCC3C2)n1
Product: O=C(c1cc(F)ccc1-c1ncccn1)N1CC2CN(c3nccc(C(F)(F)F)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 33 and Intermediate 13. MS (ESI): mass calculated for C22H18F4N6O, 459.42; m/z found 459.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.74 (d, J=4.9, 2H), 8.60-8.28 (m, 2H), 7.23-7.04 (m, 3H), 6.84-6.75 (m, 1H), 4.03-2.97 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([NH2:19])[CH:3]=1.CN1CCCC1=O.Cl.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[F:35].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:35][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:29]=1[NH:19][N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Cc1cn(N)c2ccc(OCc3ccccc3)cc12
Reactant: Fc1cnccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cn(Nc2ccncc2F)c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C
Yield: 60.5 %

Procedure:
To a solution consisting of 3-methyl-5-(phenylmethoxy)-1H-indol-1-amine (4.81 g) and 1-methyl-2-pyrrolidinone (83 ml) was added 4-chloro-3-fluoro pyridine hydrochloride (3.20 g). The resulting mixture was heated at 80° C. for 2 hours. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed successively with water (2x) and brine (1x), and thereafter dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 50% ethyl acetate/dichloromethane) afforded 4.0 g of the desired product as a solid, m.p. 210°-213° C.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)OC1C=CC=CC=1)#[N:2].[F:25][C:26]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:27]=1[NH:33][NH2:34]>C(N)(=O)C.C(OCC)(=O)C>[F:25][C:26]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:1]([NH2:2])=[N:3][C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[N:34]1
Reactant: NNc1ccc(I)cc1F
Reactant: N#CNC(=Nc1ccc(N2CCOCC2)cc1)Oc1ccccc1
Agent: CC(N)=O
Solvent: CCOC(C)=O
Product: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1ccc(I)cc1F
Temperature: 120 °C
Yield: 2.9 %

Procedure:
A mixture of N-cyano-N′-(4-morpholino-phenyl)-O-phenylisourea (0.69 g, 2.14 mmol) and 2-fluoro-4-iodo-phenylhydrazine (0.65 g, 2.57 mmol) in dimetheyl acetamide (4 mL) was heated at 120° C. for 24 h. The reaction is diluted with ethyl acetate, washed with water (3 times) and brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 4:96 methanol:dichloromethane, followed by semi-preparative HPLC provided the title compound (0.03 g, 5% yield) as a white lyophilate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]2)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([NH2:34])[C:26]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:27][CH:28]=2)=[CH:19][N:18]=1.OOS([O-])=O.[K+]>O>[C:30]([N:29]1[C:26]2[CH:27]=[CH:28][C:23]([C:20]3[CH:19]=[N:18][C:17]([NH2:16])=[N:22][CH:21]=3)=[CH:24][C:25]=2[N:34]=[C:7]1[C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccn(-c2ccc(Cl)cc2C=O)n1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: Cc1ccn(-c2ccc(Cl)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 60 °C
Yield: 13 %

Procedure:
A 10 mL aliquot of 5-chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde from the above reaction is filtered (in DMF, 50% pure by LC-MS, calculated mass based on purity is 235 mg, 1.10 mmol). The crude aldehyde is treated with 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (200 mg, 0.78 mmol). Oxone (478 mg, 0.78 mmol) is added as a water solution (2 mL). The resulting mixture is warmed to 60° C. for 2 hours and cooled to room temperature. The reaction mixture is poured into water and extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (12 g silica gel, 0-6% MeOH/CH2Cl2) followed by mass triggered HPLC(CH3CN/H2O) affords the title compound (45 mg, 13%). LCMS (ESMS): m/z 458.20 (M++1)
Reaction SMILES: O[C@H]1C[C@H]2[C@H]3[C@H](CC[C@]2(C)C1)[C@]1(C)C(=CC(=O)CC1)N(C)[C@@H]3C.[CH3:24][C@@:25]12[C:33](=[O:34])[CH2:32][CH2:31][C@H:30]1[C@@H:29]1[CH2:35][CH:36]=[C:37]3[CH2:42][C@@H:41]([OH:43])[CH2:40][CH2:39][C@:38]3([CH3:44])[C@H:28]1[CH2:27][CH2:26]2.N#N.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:61]([CH:68]([CH3:70])[CH3:69])([CH:65]([CH3:67])[CH3:66])[CH:62]([CH3:64])[CH3:63])(=O)=O>C(Cl)Cl>[CH:62]([Si:61]([CH:68]([CH3:70])[CH3:69])([CH:65]([CH3:67])[CH3:66])[O:43][C@H:41]1[CH2:40][CH2:39][C@@:38]2([CH3:44])[C:37]([CH2:36][CH2:35][C@@H:29]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:24])[C@H:30]3[CH2:31][CH2:32][C:33]2=[O:34])=[CH:42]1)([CH3:64])[CH3:63]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: C[C@@H]1[C@H]2[C@@H]3C[C@H](O)C[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C2N1C
Agent: N#N
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](O[C@@H]1C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 3β-(hydroxy)androst-5-en-17-one (1, R2 =H) (available from Sigma Chemical Co., St. Louis, Mo., 10.09 g, 35 mmoles, also called dehydroepiandrostenone "DHEA") in methylene chloride (150 mL) in a N2 atmosphere was added lutidine (6.1 mL, 52.5 mmoles) followed by triisopropylsilyl trifluoromethanesulfonate (11.6 mL, 42 mmoles) and the resulting mixture stirred at 0° C. for 25 minutes. The reaction mixture was diluted with methylene chloride (100 mL) and washed with 1N HCl (2 times), H2O, 10% NaHCO3, H2O, brine and dried over MgSO4. Evaporation in vacuo gave 3β-(triisopropylsilyloxy)androst-4-ene-17-one (2, R2 =H) as a white, waxy solid. A mixture of (2) (16.9 g, 35 mmoles), powdered KOH (1.96 g, 35 mmoles) and benzaldehyde (7.83 mL, 77 mmoles) in ethanol (250 mL) was stirred at room temperature in the dark for 18 hours. The mixture was cooled in an ice bath, filtered and the precipitate dried in a vacuum oven at 70° C. for 5 hours to give (3, R2 =H) as a white solid. NMR (CDCl3): δ 1.00 (s, 3H, 18-Me); 1.07 (s, 21H, CH(CH3)2 ; 1.09 (s, 3H, 19-Me); 3.58 (m, 1H, 3-H); 5.38 (d, 1H, 6-H); 7.37-7.57 (m, 6H, =CH--Ph).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)([O-:28])=[O:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=[N+]([O-])c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1cccs1
Yield: 80 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (350 mg) and 2-(tributylstannyl)thiophene (57 g, 0.15 mol) were added to a solution of 1-iodo-2-nitrobenzene (35 g, 0.14 mol) in 500 ml of N,N-dimethylformamide. This mixture was heated for 16 h to 100° C. After concentration in vacuo, the residue was taken up in diethyl ether, washed with water and brine, dried over magnesium sulfate and evaporated. The remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, yielding 23 g of 2-(2-nitro-phenyl)-thiophene.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C@H:12]([C:20]([NH:22][C@@H:23]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:24]([OH:43])[CH2:25][N:26]2[C@H:35]([C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][C@H:33]3[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]3)[CH2:27]2)=[O:21])[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])([CH3:15])[CH3:14])[S:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:39]([NH:38][C:36]([C@@H:35]1[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][N:26]1[CH2:25][C@@H:24]([OH:43])[C@@H:23]([NH:22][C:20](=[O:21])[C@H:12]([C:13]([S:16]([CH3:19])(=[O:18])=[O:17])([CH3:15])[CH3:14])[NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][OH:4])[N:7]=1)[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(=O)OCc1csc(N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)C(C)(C)S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Nc1nc(CO)cs1)C(C)(C)S(C)(=O)=O
Yield: 46.2 %

Procedure:
A stirred solution of 73 mg (0.1 mmol) of 2-[3(S)-[[N-[4-(acetoxymethyl)-2-thiazolyl]-3-(methanesulfonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-3(S)-isoquinolinecarboxamide (Example 141) in 7 ml of methanol/water (5:2) was treated with 700 mg of potassium carbonate. After 1.5 hours the volatiles were evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a gum which was chromatographed on silica eluting with dichloromethane/methanol (40:3) to give 32 mg (48%) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-[4-(hydroxymethyl)-2-thiazolyl]-3-(methanesulfonyl)-L-valyl]amino]-4-phenylbutyl]-3(S)-isoquinolinecarboxamide as a solid, mp 126° C., [M+H]+ 692.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[OH:24])C.O1CCCC1.[OH-].[Li+].Cl>O.C(O)C>[C:22]([C:13]1[C:14]2[C:19](=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:25])=[O:3])=[C:6]([OH:24])[CH:7]=2)[CH:12]=1)#[N:23]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(F)c(F)cc32)cc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cn(-c2ccc(C(=O)O)c(O)c2)c2cc(F)c(F)cc12
Temperature: 25 °C
Reaction time: 26 h
Yield: 88.3 %

Procedure:
To a solution of 4-(3-cyano-5,6-difluoroindol-1-yl)-2-hydroxybenzoic acid ethyl ester (0.074 g) in a mixed solvent of tetrahydrofuran (3.0 mL) and ethanol (0.75 mL) were added 0.1 g/mL aqueous lithium hydroxide solution (0.62 mL) and water (1.0 mL), and this mixture was stirred at room temperature for 26 hours. To this reaction mixture was added 2 mol/L hydrochloric acid (5 mL), this organic solvent was removed under reduced pressure. This resulting mixture was extracted with ethyl acetate, this organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give the title compounds (0.06 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[I:29][CH2:30][CH2:31][CH2:32]O>CO.C(Cl)Cl>[I:29][CH2:30][CH2:31][CH2:32][O:27][C:26](=[O:28])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OCCCI
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCCCI

Procedure:
Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-iodo-1-propanol (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.45 in 5% MeOH/methylene chloride) and the product was purified by preparative tlc using 5% MeOH/methylene chloride.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:24][NH:25][C:26](=[O:32])[CH:27]([CH3:31])[C:28](O)=[O:29]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:24][NH:25][C:26](=[O:32])[CH:27]([CH3:31])[C:28]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:29]
Reactant: COc1ccc(CNC(=O)C(C)C(=O)O)cc1OC
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: COc1ccc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)cc1OC

Procedure:
The title compound, MS: m/e=488.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,4-dimethoxy-benzyl)-2-methyl-malonamic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:48][C:49]([CH3:69])=[CH:50][CH2:51][CH2:52]/[C:53](/[CH3:68])=[CH:54]/[CH2:55][CH2:56]/[C:57](/[CH3:67])=[CH:58]/[CH2:59][S:60][CH2:61][C@H:62]([NH2:66])[C:63]([OH:65])=[O:64]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH:66][C@@H:62]([CH2:61][S:60][CH2:59]/[CH:58]=[C:57](\[CH3:67])/[CH2:56][CH2:55]/[CH:54]=[C:53](\[CH3:68])/[CH2:52][CH2:51][CH:50]=[C:49]([CH3:69])[CH3:48])[C:63]([OH:65])=[O:64])=[O:14]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)Cc1c[nH]c2ccc(O)cc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 24 mL vial, 5-hydroxyl indole-3-acetic acid (191 mg, 1.0 mmol), HATU (380 mg, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in THF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. THF was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with water (50 mL) and brain (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (210 mg, 42%) to yield Compound J. 1H-NMR (500 MHz, CD3OD): δ 1.49 (s, 9H), 1.56 (S, 3H), 1.85-1.98 (m, 6H), 2.62 (dd, J=8.0, 14.0 Hz, 1H), 2.80 (dd, J=4.5, 14.0 Hz, 1H), 2.88 (dd, J=7.0, 13.0 Hz, 1H), 2.98 (dd, J=8.5, 13.0 Hz, 1H), 3.55 (dd, J=6.5, 22.5 Hz, 2H), 4.49 (dd, J=5.0, 8.0 Hz, 1H), 4.98 (bs, 2H), 6.57 (d, J=8.5 Hz, 1H), 6.84 (s, 1H), 7.07 (d, J=6.5 Hz, 2H). 13C-NMR (125 MHz, CD3OD): δ 16.2, 17.8, 26.0, 27.3, 27.4, 27.8, 28.8, 30.2, 33.3, 33.8, 40.7, 40.9, 53.4, 103.7, 108.2, 112.7, 112.8, 121.5, 125.2, 125.5, 125.8, 129.3, 132.1, 133.0, 136.2, 140.5, 151.5, 173.9, 174.9; ES-MS: mass calcd for Chemical Formula: C28H38N2O4S 498.3 (M+). Found (M+1) m/z 499.2.