Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](=[O:20])[NH:14]2)[CH:3]([NH:6][CH2:7][CH3:8])[CH2:4][CH3:5].[CH3:21][O-:22].[Na+].[Na]>CO>[CH:9]1([CH2:2][CH2:3][C:21]([O:19][C:16]2[CH:17]=[CH:18][C:9]([CH:2]([OH:1])[CH:3]([NH:6][CH2:7][CH3:8])[CH2:4][CH3:5])=[C:10]3[C:15]=2[NH:14][C:13](=[O:20])[CH:12]=[CH:11]3)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:10]1
Reactant: C[O-]
Reactant: CCNC(CC)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCNC(CC)C(O)c1ccc(OC(=O)CCC2CCCCC2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of 5-(1-hydroxy-2-ethylaminobutyl)-8-hydroxycarbostyril was suspended in 20 ml of methanol, and sodium methylate prepared from 458 mg of sodium metal and 9.6 ml of absolute methanol was added to the suspension. The mixture was then concentrated to dryness, and the resulting residue was dissolved in 30 ml of dimethylformamide. 3.3 g of β-cyclohexylpropionyl chloride was then added dropwise to the mixture while cooling with ice-water. The mixture was then stirred for 1 hour at room temperature, and diethyl ether was added to the mixture. The precipitate formed was separated by filtration, washed with diethyl ether and recrystallized from a mixture of methanol and diethyl ether to obtain 3.86 g of 8-(β-cyclohexylpropionyloxy)-5-(1-hydroxy-2-ethylaminobutyl)carbostyril having a melting point of 233°-234° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15]C(=O)C)[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([OH:15])[C:5]=2[CH:6]=1
Reactant: COC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(O)c2cc(C)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methyl-4-acetoxy-6-methoxycarbonylbenzofuran (Method 14; 1.275 g, 5.14 mmol) was added to a suspension of potassium carbonate (1.408 g, 10.3 mmol, 2 eq) in MeOH (100 ml) and water (2 ml), and the mixture stirred for 1 hr at ambient temperature. The supernatant liquor was decanted from the insoluble material and evaporated in vacuo to yield a cream solid (2.19 g, assumed to be contaminated with inorganics). NMR: 2.35 (s, 3H), 3.56 (br s, 1H), 3.73 (s, 3H), 6.46 (s, 1H), 6.69 (s, 1H), 6.86 (s, 1H); m/z 205 (M−H)−, 83% by LC-MS.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([CH:44]=[CH:45][C:46]3[CH:51]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:49]=[C:48]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:47]=3)[CH:43]=2)[CH:39]=O)[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)([CH3:23])([CH3:22])[CH3:21].[C:60]([Br:64])(Br)(Br)[Br:61]>ClCCl>[Br:61][C:60]([Br:64])=[CH:39][C:38]1[CH:41]=[C:42]([CH:44]=[CH:45][C:46]2[CH:51]=[C:50]([C:52]([CH3:53])([CH3:54])[CH3:55])[CH:49]=[C:48]([C:56]([CH3:59])([CH3:57])[CH3:58])[CH:47]=2)[CH:43]=[C:36]([CH:35]=[CH:34][C:26]2[CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=2)[CH:37]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(C=C(Br)Br)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 94.9 %

Procedure:
Triphenylphosphine (3.92 g, 14.96 mmol) was added in one portion to a stirred solution of -3,5-bis[2-(3,5-di-tert-butylphenyl)vinyl]benzaldehyde (1) (2.00 g, 3.74 mmol) and carbon tetrabromide (2.48 g, 7.38 mmol) in dichloromethane (20 mL). Heat was evolved and the mixture stirred at room temperature for 75 min. The resultant orange suspension was washed with water (2×50 mL), dried over anhydrous magnesium sulphate, filtered and the solvent removed to leave an orange-brown residue, which was purified by passing through a plug of silica with dichloromethane—light petroleum (2:3) as eluent. The solvent was removed to give 2-{3,5-bis[2-(3,5-di-tert-butylphenyl)vinyl]phenyl}-1,1-dibromoethene (2) as a white foam (2.45 g, 95%) mp 148-150° C. (Found: C, 69.5; H, 7.3; C40H50Br2 requires C, 69.6; H, 7.3%); νmax(KBr)/cm−1 1595 (C═C) and 958 (C═C—H trans); λmax(CH2Cl2)/nm 306 (log(ε/dm3 mol−1 cm−1)4.85), 317 (4.85) and 329sh (4.73); −δH(400 MHz, CDCl3) 1.40 (36 H, s, t-butyl), 7.14 and 7.24 (4 H, d, J 16, vinyl H) 7.40 (2 H, dd, J 1.5, sp H),7.42(4 H, d, J 1.5, sp H), 7.56 (1 H, s, CHCBr2), 7.60 (2 H, s, cp H) and 7.69 (1 H, s, cp H); m/z (CI+) 692.2 (MH+, 100%), 613.2 (M−79Br, 96%), 611.2 (M−81Br, 90%) and 533.3 (M−279Br, 74%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([CH2:4][OH:3])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccc(Cl)cc2[nH]1
Reaction time: 3.5 h
Yield: 111.7 %

Procedure:
To 6-chloro-1H-indole-2-carboxylic acid ethyl ester (8.57 g) in THF at 0° C. was added lithium aluminum hydride solution (1M, in THF) dropwise and the reaction mixture was stirred for 3.5 h. The mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed with THF. Evaporation of the solvent gave 7.77 g of the crude (6-Chloro-1H-indol-2-yl)-methanol which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(CC1CCOCC1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (152 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 270 μL, 0.53 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (5 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 78 mg, 0.50 mmol), 2,6-lutidine (130 μL, 1.00 mmol), and methylene chloride (5 mL) which was 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated in vacuo. It was then dissolved in ethyl acetate (25 mL) and washed with a 1N hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 100% ethyl acetate) to afford 2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (149 mg, 81%) a 1:1 enantiomeric reaction as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([C:11]([OH:13])=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([C:11]([O:13][CH3:24])=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)=C(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 153 mg of 1-(t-butoxycarbonyl)-4-phenyl-1,2,5,6-tetrahydronicotinic acid in 1 mL of THF and 1 mL of MeOH was added 0.6 mL of TMSCHN2 (2M in hexanes). The reaction was stirred at room temperature for 2 h and concentrated under vacuum. The residue was purified by flash chromatography eluting with 20% EtOAc in hexanes to provide 116 mg of the title compound: 1H NMR (300 MHz, CDCl3): δ1.5 (s, 9H), 2.5-2.6 (m, 2H), 3.5 (s, 3H), 3.6 (t, 2H), 4.2-4.3 (m, 2H), 7.1-7.2 (m, 2H), 7.2-7.4 (m, 3H). RF : 0.68 (50% EtOAc in hexanes).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:11][C:12]([F:21])([F:22])[O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Yield: 9 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and 4-(trifluoromethoxy)aniline (62.8 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 9.5 mg (32 μmol; 9% yield) of pure desired product. LC-MS (method V): rt=2.69 min; m/z [M+H]+ 299.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13](OC)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[CH2:13][OH:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccccc1Oc1ccc2[nH]ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
The methyl 2-(1H-indazol-5-yloxy)benzoate (95.6 g, 0.36 mmol) obtained in Example 478 was dissolved in tetrahydrofuran (5 ml), and lithium aluminum hydride (44.1 mg, 1.07 mmol) was added thereto at 0° C. and stirred for 30 minutes. Water (0.3 ml), a 2N-aqueous sodium hydroxide solution (0.6 ml) and water (0.9 ml) was added dropwise thereto in that order, and the precipitate formed was removed by filtration. A saturated aqueous sodium hydrogencarbonate solution was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to obtain [2-(1H-indazol-5-yloxy)phenyl]methanol (56 mg, 65%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C:5]1=[O:11].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([Si:21]([CH3:24])([CH3:23])[O:1][CH2:2][CH2:3][C@@H:4]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C:5]1=[O:11])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1(C)OC(=O)[C@H](CCO)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
Step C A mixture of (S)-5-(2-hydroxy-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one (6.8 g, 42 mmol) and imidazole (7.5 g, 107 mmol) in dimethylformamide (40 mL) was added tert-butyldimethylchlorosilane (7 g, 45 mmol). The reaction mixture was stirred at room temperature for 18 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, concentrated to give (S)-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-one as a colorless oil (8.6 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Cl)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)cc(Cl)c1
Temperature: 35 °C
Yield: 97 %

Procedure:
147.2 g (0.86 mole) of 3-chloro-5-methylbenzoic acid previously prepared were suspended in 250 ml of methanol and warmed up to 35° C. with stirring. To the resulting suspension were added slowly 113 g (0.95 mole) of thionyl chloride keeping the temperature below 60° C. (cooling by ice bath). When addition was completed, the resulting mixture was refluxed for 1 hour, then stirred and cooled down to room temperature. The solvent was removed in the rotovap and the residue poured into water. The resulting aqueous suspension was extracted with ethyl ether (2×750 ml). The combined organic extracts were washed with 2% aqueous sodium hydroxide (3×150 ml), followed by water (1×200 ml), and then brine (1×200 ml), dried over anhydrous sodium sulfate and then concentrated in the rotavap to give the expected Methyl-3-chloro-5-methylbenzoate (154.6 g, 97% purity), used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]([CH3:34])([CH3:33])[C@@H:28]([OH:32])[C:29](O)=[O:30].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:26][C:27]([CH3:34])([CH3:33])[C@@H:28]([OH:32])[C:29]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([NH:13][CH2:12][C:11]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:30]
Reactant: CC(C)(C)[C@@H](O)C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide from step 2 (3.90 g, 10.6 mmol, HPLC RT=2.77 min), (2R)-3,3-dimethyl-R-hydroxybutyric acid from step 3 (1.40 g, 10.6 mmol), and HOBT hydrate (1.68 g, 11 mmol) in DMF (60 mL) was added EDC (2.65 g, 13.8 mmol). Diisopropylethylamine was then added slowly in portions (11.5 mL total) to bring the pH of the solution to 6-7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 6 h, at which time HPLC analysis indicated complete consumption of the proline starting material. Water (10 mL) was added and the solvents were removed under reduced pressure. The residue was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO3 (200 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient elution of 2:1, 4:1, and 1:0 EtOAc:hexanes. 1-((2R)-3,3-dimethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide was obtained as a colorless gum (4.65 g, 91%; TLC Rf=0.7 (EtOAc); HPLC RT=3.35 min, method A; LC-MS m/z=482).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2>CCO.CO.[OH-].[OH-].[Pd+2]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[C@@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Reaction time: 68 h
Yield: 90.4 %

Procedure:
1-{2-[4-(6-Methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine hydrochloride (nafoxidene hydrochloride) (75 g, 162 mmol) was dissolved in 1000 mL of EtOH and 300 mL of MeOH. Dry Pd(OH)2 on carbon was added and the mixture was hydrogenated on a Parr shaker at 50° C. and 50 psi for 68 h. The catalyst was filtered off with the aid of celite and the solvents were removed in vacuo. The resulting white solid was dissolved in CH2Cl2 and the solution was washed with satd NaHCO3 (aq). The organic solution was dried (MgSO4), filtered, and concentrated to yield an off-white solid (62.6 g, 90%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[N:10]([O-])=O.[Na+].[OH-].[Na+].C(S(O)=O)(N)=N>CO.O>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[NH2:10]
Reactant: O=N[O-]
Reactant: CNC1CCCCC1
Agent: Cl
Agent: N=C(N)S(=O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(N)C1CCCCC1
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of N-methylcyclohexylamine (17 g) in a 6N aqueous hydrochloric acid solution (90 ml) is added dropwise an aqueous solution (60 ml) of sodium nitrite (20.7 g) at 60° C. The mixture is stirred at the same temperature for 2 hours, and diluted with methanol (300 ml). To the mixture are added an aqueous solution (100 ml) of sodium hydroxide (45 g) and formamidine sulfinic acid (39 g). The mixture is refluxed for 2 hours, and diluted with water (400 ml). The mixture is extracted three times with methylene chloride, and the extract is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue is distilled under reduced pressure to give 1-methyl-1-cyclohexylhydrazine (10 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([Br:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:18]=[C:16]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([Br:14])[CH:7]=2)[NH:1]1
Reactant: NC(=O)c1cc(Br)c([N+](=O)[O-])cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2cc(Br)c([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 289.1 %

Procedure:
17.3 g (66.5 mmol) of 2-amino-5-bromo-4-nitro-benzamide were dissolved in 500 ml of tetrahydrofuran and treated at 0° C. with 13 g (10.4 mmol) of triphosgene. The mixture was left to warm to room temperature and stirred for a further 1.5 hrs. Then, the solution was concentrated and triturated with water. The precipitate was filtered off under suction and dried. 8.6 g (45%) of 2,4-dioxo-6-bromo-7-nitro-1,2,3,4-tetrahydroquinazoline were obtained as yellowish crystals;
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1>CCOC(C)=O>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: CSc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Product: CSc1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure Coupling-2 using [3-(methylthio)phenyl]boronic acid and 3,5-dibromopyridine as starting material. Flash chromatography (Hex:EtOAc; 95:5-85:15) afforded the title compound.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>O1CCCC1>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][I:29])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (178 mg, 0.42 mmol) prepared in Example 99 was dissolved in tetrahydrofuran (10 mL). Iodine (161 mg, 0.63 mmol), triphenylphosphine (166 mg, 0.63 mmol) and imidazole (86 mg, 1.23 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (120 mg, Yield 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2[CH:20]=1.[N:21]([O-])=O.[Na+]>C(O)(=O)C.O>[NH2:21][C:20]1[N:11]2[CH:12]=[CH:13][C:14]3[C:19]([C:10]2=[N:9][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: O=N[O-]
Reactant: Cc1ccccc1-c1cn2ccc3ccccc3c2n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Reaction time: 1 h
Yield: 79.4 %

Procedure:
In a mixture of 30 ml of acetic acid and 6 ml of water was dissolved 2.5 g of 2-(2-methylphenyl)imidazo[2,1-a]isoquinoline with ice-cooling and stirring. A solution of 3.4 g of sodium nitrite in 12 ml of water was added portionwise to this solution and then the mixture was stirred at room temperature for 1 hour. The resulting crude crystals were collected by filtration and washing. The obtained powder was suspended in a mixture of 30 ml of acetic acid and 15 ml of water. To this suspension was added portionwise 6.3 g of zinc powder. After 1 hour, the reaction mixture was filtered, the filtrate was rendered alkaline by the addition of 28% ammonia water, and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from ethyl acetate/petroleum ether to give 2.1 g of the title compound as orange needles.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.[C:18]1([CH2:24][C:25](OC)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.C(O)(=O)C>[O:26]=[C:25]([CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of dimethyl methylphosphonate (62 g.) in 400 ml. of tetrahydrofuran at -74° C. is treated by slow addition of 316 ml. of 1.6 M n-butyllithium in hexane, while maintaining the temperature below -62° C. A solution of phenylacetic acid, methyl ester (37.5 g.) in 100 ml. of tetrahydrofuran is added while maintaining the temperature below -60° C. The mixture is stirred at that temperature for 3 hr. and then allowed to warm to about 25° C. Acetic acid (30 g.) is added and the resulting precipitate removed by filtration. The filtrate is concentrated, taken up in diethyl ether, washed with water and brine, dried over magnesium sulfate and concentrated to the product, 38.74 g. The product is further distilled 140°-155° C./0.4 mm. to yield 19.5 g. of the title compound.