Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:21])[C@@H:18]([CH3:20])[NH2:19])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:20][C@H:18]1[NH:19][C:30](=[O:32])[N:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:11][CH:12]=2)[C:17]1=[O:21]
Reactant: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
To a solution of N1-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-D-alaninamide (Intermediate 2, 315 mg) and triethyl amine (0.307 mL, 2.200 mmol) in dry ethyl acetate (5 mL), triphosgene (163 mg, 0.550 mmol) was added and the reaction mixture was stirred for 5 minutes. DMAP (67.2 mg, 0.550 mmol) was then added and the reaction mixture was stirred for further 10 minutes. The reaction was quenched with a saturated solution of sodium carbonate (5 mL), diluted with water (10 mL) and extracted with ethyl acetate (3 times 20 mL). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 10 g SNAP column) eluting with a gradient cyclohexane/ethyl acetate from 100/0 to 60/40 to afford the title compound as a white solid (115 mg).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:52][CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.CC#N.Cl.O1CCOCC1>C(Cl)Cl>[N:55]1([CH2:54][CH2:53][O:52][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH2:17])[CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:2][CH:3]=2)[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: OCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCCN1CCCCC1
Reaction time: 0.03 h

Procedure:
(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (125 mg, 302 μmol), HOBt (240 mg, 1.8 mmol), and EDCI (320 μL, 1.8 mmol) were dissolved in DCM and stirred for 2 minutes. N-(2-Hydroxyethyl)piperidine (401 μL, 3.0 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried, concentrated, then purified (Interchim reverse phase chromatography column; 5-70% MeCN in water with 0.5% TFA). The purified material was combined with MeCN (3.0 mL, 58 mmol) and 4 M HCl in dioxane (0.3 mL, 1.2 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and azeotroped with toluene (2×) to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-piperidin-1-yl-ethyl ester.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:1]([CH2:2][CH2:3][NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: NCCCCCCCCCCCCCCCCCCc1ccccc1
Reactant: C=CC#N
Solvent: O
Product: N#CCCNCCCCCCCCCCCCCCCCCCc1ccccc1

Procedure:
N-(Beta-cyanoethyl)phenyloctadecylamine was prepared as follows: Acrylonitrile (61.0 grams, 1.15 moles) was added slowly over 2 hours, with stirring, to a mixture of phenyloctadecylamine, prepared as described in Example II, (363.8 grams, 1.05 moles) and 17.0 grams water at 60°-70°C. The resulting mixture was then stirred at 70°-80° for 4 additional hours. The water was separated and the product dried under reduced pressure at 60°-70°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:42][C:43]([F:50])([F:49])[CH2:44][NH:45][CH2:46][CH2:47][NH2:48]>CN(C=O)C>[F:42][C:43]([F:50])([F:49])[CH2:44][NH:45][CH2:46][CH2:47][NH:48][C:24]([C:23]1[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=1/[CH:18]=[C:10]1\[C:11](=[O:17])[NH:12][C:13]2[C:9]\1=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH:16]=[CH:15][CH:14]=2)=[O:25]
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: NCCNCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)NCCNCC(F)(F)F)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
A mixture of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (53 mg, 0.15 mmol), HOBt (28 mg), EDC (36 mg), TEA (0.042 mL) and N1-(2,2,2-trifluoro-ethyl)-ethane-1,2-diamine (0.036 mL) in DMF (1 mL) was stirred at rt for 48 hours. The solvent was removed and diluted with sat. NaHCO3. It was then extracted with DCM, dried and concentrated. The residue was purified on a silica gel column to give 52 mg (71%) of the titled compound.
Reaction SMILES: [N:1]1([CH2:11][C:12]([OH:30])([CH2:17][C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])([CH3:20])[CH3:19])[C:13]([F:16])([F:15])[F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.C=O.[C:33]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[F:16][C:13]([F:14])([F:15])[C:12]([CH2:11][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:33])[CH2:3][CH2:2]1)([OH:30])[CH2:17][C:18]([C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[O:28][CH3:29])([CH3:20])[CH3:19]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCNc2ccccc21)C(F)(F)F
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCN(C)c2ccccc21)C(F)(F)F
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of 2-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (Example 4) (18.6 mg) in acetonitrile (3 mL) was added formaldehyde solution (37% w/w aqueous, 300 μL) followed by sodium cyanoborohydride (13.8 mg). After 30 minutes at room temperature, acetic acid (50.4 μL) was added. The resulting mixture was stirred for 3 hours, quenched with saturated aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and the volatiles removed in vacuo. The residue was purified by preparative TLC (eluted with 25% EtOAc-hexanes) to give the title compound as a pale yellow oil (16.6 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[N:35]1([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]4[CH2:44][CH2:45][CH:40]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:41][CH2:42]4)=[C:8]([O:33][CH3:34])[CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[C:19]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH:20]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), 4-(1-pyrrolidinyl)piperidine (60 mg), and potassium carbonate (90 mg) was suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (69 mg, yield 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.[CH:30]1([CH2:33][O:34][C:35]2[N:36]=[C:37]([CH3:44])[C:38]([C:41](O)=[O:42])=[N:39][CH:40]=2)[CH2:32][CH2:31]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[CH:30]1([CH2:33][O:34][C:35]2[N:36]=[C:37]([CH3:44])[C:38]([C:41]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:27][CH2:26][CH2:25][C@H:8]5[S:9](=[O:23])(=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:12][C@:7]5([CH3:28])[C:6]=4[CH:29]=3)=[O:42])=[N:39][CH:40]=2)[CH2:31][CH2:32]1
Reactant: Cc1nc(OCC2CC2)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(OCC2CC2)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of crude tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.035 g, 0.083 mmol) in DCM (0.8 ml) were added 5-(cyclopropylmethoxy)-3-methylpyrazine-2-carboxylic acid (0.018 g, 0.087 mmol), triethylamine (0.023 ml, 0.165 mmol) and HATU (0.035 g, 0.091 mmol). The mixture was stirred at RT for 25 min. The reaction mixture was diluted with water and sat. NaHCO3, and extracted with DCM. The organic extract was washed with brine and dried over MgSO4. It was filtered and concentrated to give the crude material as a yellow oil which was used for next step directly. MS m/z: 614.1 [M+H].
Reaction SMILES: COC(OC)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][O:46][CH:47]([O:50][CH3:51])[CH2:48]Br.[CH3:52][CH:53]([CH3:60])[CH2:54][C:55](=O)[C:56]([OH:58])=[O:57]>>[CH3:45][O:46][CH:47]([O:50][CH3:51])[CH2:48][CH:55]([CH2:54][CH:53]([CH3:60])[CH3:52])[C:56]([OH:58])=[O:57]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: COC(CBr)OC
Agent: COC(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(CC(CC(C)C)C(=O)O)OC

Procedure:
Alternatively, for those compounds wherein n=1 and R1 is H, the compounds can be prepared by condensing the ylide 1,1-dimethoxy-2-(triphenylphosphoranylidene)ethane prepared from triphenylphosphine and 1,1-dimethoxy-2-bromoethane with 4-methyl-2-oxopentanoic acid. The product is then hydrogenated to obtain 4,4-dimethoxy-2-isobutylbutanoic acid which is coupled to the moiety R3NHCHR4COX to obtain 4,4-dimethoxy-2-isobutylbutanoyl-NR3CHR4COX. Treatment with aqueous acid yields the aldehyde 2-isobutyl-4-oxobutanoyl-NR3CHR4COX. The oxime is prepared by reaction with hydroxylamine and reduced to the corresponding N-substituted hydroxylamine. Acylation of both the hydroxaminol oxygen and nitrogen followed by hydrolysis of the O-acyl group provides the N-acyl reverse hydroxymates. (Summers, J. B., et al., J Med Chem (1988) 31:1960-1964.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si](C)(C)C)[S:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][S:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)c1cc2cc(Br)cnc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Brc1cnc2sccc2c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The 5-bromo-2-(trimethylsilyl)thieno[2,3-b]pyridine from Part A (8.99 g, 31.4 mmol) was dissolved in ethanol (70 mL), followed by addition of K2CO3 (10.85 g, 78.5 mmol). Reaction was stirred at 65° C. for 1 hour. The reaction mixture was allowed to cool to 25° C., concentrated to dryness, and dissolved in EtOAc (150 mL). The solution was washed with H2O (80 mL), and brine (150 mL), dried over Na2SO4, filtered, and concentrated to yield white solid, 5-bromothieno[2,3-b]pyridine, 6.57 g (98%). 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J≦2.2 Hz, 1H), 8.16 (d, J=2.2 Hz 1H), 7.57 (d, J=6.0 Hz 1H), 7.21 (d, J=6.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1ccccc1OCc1ccccc1
Yield: 67.2 %

Procedure:
15 g of methyl 2-hydroxyphenylacetate are refluxed with 11.4 g of benzyl chloride and 6.2 g of potassium carbonate in 90 ml of absolute methanol for 24 hours. The mixture is filtered, the filtrate is evaporated down, 400 ml of ether are added to the residue, and the solution is washed with water, dried with MgSO4 and evaporated down. Distillation of the residue at about 200° C. and under 18 mbar gives 15.5 g of pale oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11]([CH3:21])([CH3:20])[O:10][C:9]2=[O:22])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.F[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[N+:41]([O-:43])=[O:42]>C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:12]2[C:11]([CH3:20])([CH3:21])[O:10][C:9](=[O:22])[N:8]2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=3[N+:41]([O-:43])=[O:42])[CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)N(C2CCC(N)CC2)[C@H]1c1ccc(F)cc1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccc(C#N)cc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Yield: 94 %

Procedure:
To a vial charged with (S)-3-(4-aminocyclohexyl)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.353 g, 1.152 mmol) were added ACN (3.84 mL), DIEA (0.402 mL, 2.304 mmol) and 4-fluoro-3-nitrobenzonitrile (commercially available from J & W Pharmlab, Levittown, Pa.) (0.191 g, 1.152 mmol) respectively. After completion of reaction, the dark mixture was dried under reduced pressure and purified with a 25 g HP spherical silica column ramping DCM:MeOH (90:10) in DCM from 0-50%, then isocratic at 50% (detection at 215 nm) leading to isolation of product which was obtained as an orange/brown oil as a mixture of cis/trans isomers of (S)-4-((4-(4-(4-fluorophenyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)cyclohexyl)amino)-3-nitrobenzonitrile (0.490 g, 1.083 mmol, 94% yield). m/z (ESI) 453.2 (M+H)+.
Reaction SMILES: Br.Br.[S:3]1[C:7]2[CH2:8][CH:9]([NH2:12])[CH2:10][CH2:11][C:6]=2[N:5]=[C:4]1N.N([O-])=O.P(P(O)(O)=O)(O)(O)=O.[OH-].[Na+]>Cl>[S:3]1[C:7]2[CH2:8][CH:9]([NH2:12])[CH2:10][CH2:11][C:6]=2[N:5]=[CH:4]1
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Br
Agent: Cl
Agent: O=N[O-]
Product: NC1CCc2ncsc2C1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
To a solution of 12.8 g (38.9 mmol) 4,5,6,7-tetrahydro-benzothiazole-2,6-diamine dihydrobromide in 220 mL concentrated aqueous hydrochloric acid at −30° C. is drop wise added 66.3 mL of an aqueous 1N solution nitrite over the course of 30 minutes. After further stirring for 1 hour at the same temperature 5.44 ml (52.5 mmol) of a 50% aqueous solution hypophosphoric acid is added. The reaction mixture is stored at 4° C. overnight. After having cooled down the solution again to −30° C. the mixture is slowly basified with 40% aqueous sodium hydroxide solution while temperature is kept at −30° C. The resulting mixture is warmed up to room temperature and extracted with Chloroform/Ethanol 5:1 (3×250 mL). The solution is dried over anhydrous sodium sulfate and concentrated in vacuum. The product obtained is chromatographically purified over silica gel, eluting with dichloromethane/methanol
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[OH-].[Na+].[CH:14](=O)[CH3:15]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]=[CH:14][CH3:15])=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC=NNc1ccc(OC)cc1
Temperature: 0 °C

Procedure:
Combine (4-methoxyphenyl)-hydrazine hydrochloride salt (10 g, 57 mmol), sodium hydroxide solution (50 mL, 1M), and extract with toluene. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Combine the residue and toluene (50 mL) and cool to 0° C. Add acetaldehyde (3.5 mL, 63 mmol) dropwise as a solution in toluene (10 mL). When the addition is complete, warm to ambient temperature. After 1 hour at ambient temperature evaporate under a stream of nitrogen to give N-(4-methoxyphenyl)-N'-ethylidene hydrazine.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].C([NH:13][C:14]1[C:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:18]=2[C:17]([Cl:26])=[CH:16][CH:15]=1)(=O)C.[OH-].[Na+]>>[NH2:13][C:14]1[C:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:18]=2[C:17]([Cl:26])=[CH:16][C:15]=1[N+:6]([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)c2c1CCN(C)CC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCc2c(Cl)cc([N+](=O)[O-])c(N)c2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 200 g. of concentrated sulfuric acid and 50 g. of concentrated nitric acid at 0°-5° C. is added, in portions, 12.6 g. (0.05 mole) of 9-acetamido-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine. The solution is stirred at 0°-5° C. for 2 hours and then it is poured cautiously into 500 ml. of ice/water. The solution is made alkaline with sodium hydroxide. After being stirred at 25° C. for 16 hours, the mixture is filtered to give 9-amino-6-chloro-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[C:34]([O:36]CC3C=CC=CC=3)[CH:33]=[CH:32][C:31]=2[O:44]CC2C=CC=CC=2)[CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][C:20]([CH3:28])([CH3:27])[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=2[OH:44])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([CH3:27])([CH3:28])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC1(Cc2cc(OCc3ccccc3)ccc2OCc2ccccc2)COCCOCC(C)(C)COCCOC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCC1(Cc2cc(O)ccc2O)COCCOCC(C)(C)COCCOC1
Yield: 108 %

Procedure:
A solution of 15.8 g (22.5 mmol) of Compound 5 in 20 mL of ethyl acetate and 20 mL of methanol was mixed with 0.4 g of palladium-on-carbon in a parr flask under a nitrogen atmosphere. The mixture was reacted at 50-60° C. under 50 psi H2 for 4 hours. After cooling, the product was filtered through Celite diatomaceous earth and the solvent removed to yield 12.7 g of impure product (Compound 6).
Reaction SMILES: CCOCC.C[Si]([C:10]#[C:11][C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1)(C)C.[C:26]1([Li])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:11]([C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])=[CH:14][CH:13]=1)#[CH:10]
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: O
Product: C#Cc1ccc(C(O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a flask containing a mixture of 4-bromobenzophenone (1.31 g, 5.0 mmol). PdCl2 (PPh3)2 (70 mg. 0.10 mmol), and CuI (10 mg, 0.050 mmol) was added Et2NH (50 mL) and trimethylsilyl-acetylene (0.85 mL, 6.0 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. The solvent was removed under vacuum, and the residue was extracted with CH2Cl2 /H2O. The organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was recrystallized from CH2Cl2 /hexane to afford pale brown crystalline 4-(trimethylsilylethynyl)benzophenone in 93% yield (1.30 g). 1H NMR (300 MHz, C6D6, 25° C., TMS): δ=0.25 (s, 9 H, CH3) 7.44-7.74 (m 9 H, Ph and C6H4); MS (EI) : m/e 278 (M+ --CH3) To a Et2O solution (100 mL) of 4-(trimethylsilylethynyl)benzophenone (1.39 g, 5.0 mmol) prechilled to -30° C. was slowly added a solution of phenyllithium (3.33 mL, 6.0 mmol, 1.8 M in cyclohexane-ether). The solution was slowly warmed to room temperature and stirred for 4 hours. 1 mL of H2O was added and the solution was stirred for 30 minutes. Additional H2O (>200 mL) was added and the organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was chromatographed using CH2Cl2 /hexane (2:1) as eluent to afford (4-ethynylphenyl)-diphenylmethanol as a pale yellow oil in 81% yield (1.24 g).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:39])=[O:4])=[CH:12][CH:11]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)cc2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)O)cc3)cc2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.293 mL, 0.293 mmol) was added to a solution of (E)-(4′-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-biphenyl-4-yl)acetic acid methyl ester (Example 59-(1); 48.7 mg, 0.098 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (38.8 mg, 82%).