Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[CH:25]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccnc(N3CCNCC3)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.0 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.641 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.0 mmol) in toluene (4.0 mL) at 100° C. for 23 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(piperazin-1-yl)pyridin-4-yl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=375.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 68.2 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (2.62 g, 14 mmol), cesium carbonate (5 g, 15 mmol) and ethyl bromoacetate (1.56 ml, 14 mmol) was stirred at room temperature for 1 h. The mixture was partitioned between water (200 ml) and diethyl ether (2×100 ml). The combined organic phases were dried over magnesium sulphate and concentrated to give a yellow oil which crystallised to give 4-ethoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid (2.6 g)
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:14][O:13][C:3]1[C:2]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[C:4]=1[CH:11]=[O:12]
Reactant: COc1c(Br)cc2ccoc2c1C=O
Reactant: OB(O)c1ccncc1
Product: COc1c(-c2ccncc2)cc2ccoc2c1C=O

Procedure:
From 5bromo-6-methoxybenzofuran-7-carbaldehyde (350 mg) and pyridine-4-boronic acid (0.21g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].C(C(C(C([O-])=O)O)O)([O-])=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[C@H:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 38.7 %

Procedure:
To a solution of the (R)-amlodipine-hemi-L-tartrate-DMSO-solvate (68.25 g) obtained in Step (2) in methylene chloride (345 mL, 5 mL/g) was added a solution of 50% sodium hydroxide (73 mL) in water (72 mL). The solution was stirred at ambient temperature for 40 minutes. The layers were separated and the organic layer extracted with water (1×150 mL) and gravity filtered through a magnesium sulphate (25 g) bed. The magnesium sulphate was washed with methylene chloride (40 mL) and the methylene chloride removed on a rotary evaporator using a water aspirator. Heptane was added to the evaporation flask as the volume allowed. Eventually, all of the methylene chloride was removed and 600 mL of heptane was added to the flask. The resulting solid was collected by suction filtration, washed with heptane and dried in vacuo at 50° C. overnight to give (R)-amlodipine free base (19.4 g, 53.4% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:16](=[O:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].CO.[BH4-].[Na+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]([OH:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)=[CH:4][C:3]=1[C:23]([F:26])([F:24])[F:25]
Reactant: COC(=O)C1C(=O)c2ccccc2OC1c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)C1C(O)c2ccccc2OC1c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2.25 h
Yield: 96.8 %

Procedure:
A solution of methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate (300 mg, 780 μmol) in tetrahydrofuran (2.0 mL) was diluted with methanol (4.0 mL, 780 μmol) and treated at rt with sodium borohydride (30 mg, 780 μmol). After 2.25 h, the solution was poured into water (about 25 mL), treated with 1.0 M aqueous HCl (about 1 mL) and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide crude racemic methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxychroman-3-carboxylate as a white solid (292 mg). Without further purification, this material was dissolved in dichloromethane (9.5 mL) and treated with trifluoroacetic acid (0.5 mL). After standing at rt for 1.5 h, the solution was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography (silica gel, 2-10% ethyl acetate/hexane) to provide crude racemic methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxylate as a colorless gum (65 mg). Without further purification, a solution of a portion of this gum (60 mg) in methanol (2.0 mL) was treated with 1.0 M aqueous sodium hydroxide (2.0 mL) and heated at reflux for 4.5 h. After this time, the solution was cooled to rt. Once at the prescribed temperature, a white solid formed, which was removed by filtration and washed with water. The combined filtrate and wash were acidified with 1.0 M aqueous HCl, giving a gummy material. A small amount of methanol was added to the gummy material and the resulting mixture was heated briefly, then stirred while cooling to rt, thereby forming a white solid, which was collected by filtration, washed with water and dried under vacuum to provide Example 2-1 (29 mg). 1H NMR (400 MHz, CDCl3) δ ppm 6.26 (s, 1 H) 6.83 (d, J=8.1 Hz, 1 H) 6.96 (t, J=7.1 Hz, 1 H) 7.23 (dd, J=7.6, 1.0 Hz, 1 H) 7.29 (m, 1 H) 7.41 (d, J=8.1 Hz, 1 H) 7.46 (dd, J=8.6, 2.0 Hz, 1 H) 7.72 (d, J=1.5 Hz, 1 H) 7.83 (s, 1 H. Mass spectrum m/z 355.24 (M+H)+, 377.16 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Yield: 93.1 %

Procedure:
Following the 5a synthetic method, using B1 (55.33 mg, 0.25 mmol) instead of A1 gave 5b as a yellow powder (99.57 mg, 93.1%). [α]D25: +24.7 (c=0.36, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 8.09 (s, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.69-7.61 (m, 2H), 7.36-7.25 (m, 5H), 7.04 (s, 1H), 5.15-5.13 (m, 1H), 3.44-3.29 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 175.32, 160.09, 139.05, 137.72, 135.22, 135.18, 129.87, 129.45, 128.83, 127.53, 125.62, 123.85, 122.14, 120.43, 120.37, 119.48, 54.20, 37.26, 29.70; HRMS (ESI): calcd for: C19H13ClF3NO3S [M−H]−=426.0184, obsd [M−H]−=426.0180.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:15]([O-:17])=[O:16])[CH2:4]1.[ClH:18]>O1CCCC1.C(#N)C>[ClH:18].[CH3:1][O:2][C@H:3]1[CH2:7][NH:6][C@@H:5]([C:15]([OH:17])=[O:16])[CH2:4]1
Reactant: CO[C@@H]1C[C@H](C(=O)[O-])N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: CO[C@H]1CN[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8.72 g 1-tert-butyl (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylate are dissolved in 60 ml of tetrahydrofuran, combined dropwise with 60 ml of a 6 M aqueous hydrochloric acid solution and stirred for 4 hours at ambient temperature. Then the solvents are eliminated in vacuo and the residue is taken up twice in 100 ml acetonitrile and the latter is in each case eliminated again in vacuo.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH:16]([NH:21][C:22](=O)OC)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH:16]([NH:21][CH3:22])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)NC1CN(Cc2ccccc2)CCC1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CN(Cc2ccccc2)CCC1C
Yield: 75.9 %

Procedure:
At about 0° C., lithium aluminum hydride (3.6 g, 92.8 mmol, 5.00 equiv.) was added in several batches to a solution of methyl 1-benzyl-4-methylpiperidin-3-yl-carbamate (5.0 g, 18.1 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL). The resulting solution was heated at reflux for about 16 hours, and then water (10 mL) was added. The mixture was filtered, and the resulting filtrate was concentrated in vacuo to give a crude residue that was then purified by silica gel column chromatography (dichloromethane/methanol (20:1)) to afford the title product as a yellow oil (3.0 g; yield=72%). 1H NMR (300 MHz, CDCl3) δ: 7.20-7.38 (m, 5H), 3.58 (d, J=13.2 Hz, 1H), 3.48 (d, J=13.2 Hz, 1H), 2.60-2.82 (m, 2H), 2.46 (br s, 1H), 2.34 (s, 3H), 2.02-2.22 (m, 2H), 2.64-2.84 (m, 2H), 1.45-1.58 (m, 2H), 0.97 (d, J=6.9 Hz, 3H). LC-MS: m/z=219 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[CH:12](Br)[CH3:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.O>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[CH:12]([N:16]=[N+:17]=[N-:18])[CH3:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)C(C)Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(NC(=O)C(C)N=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a stirred a solution of N-(3-Acetylphenyl)-2-bromopropionamide (800 mg, 2.97 mmol) in DMF (10.0 mL) was added NaN3 (290 mg, 4.46 mmol). The reaction was stirred at room temperature under N2 atmosphere for 12 h, diluted with water, and the precipitated solid was filtered and dried to give the title product in 50% yield. 1H NMR (CDCl3, 400 MHz): 8.36 (br s, NH), 8.08-8.07 (m, 1H), 7.90-7.87 (m, 1H), 7.74-7.71 (m, 1H), 7.44 (t, J=8.0 Hz, 1H), 4.25 (q, J=6.8 Hz, 1H), 2.61 (s, 3H), 1.65 (d, J=6.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz): 197.7, 168.2, 137.8, 137.5, 129.4, 124.6, 124.5, 119.5, 59.4, 26.7, 17.1. ESI-MS calcd for C11H11N4O2 (M−H)+231.09. found 231.1.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=2)=[CH:10][N:9]=1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:29][O:28][C:26]([C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:27]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Oc2ccc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2

Procedure:
A solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (163a) (260 mg, 0.65 mmol) in 4 mL CH2Cl2 and 2 mL TFA was stirred at room temperature for 2 hr. The mixture was concentrated, dried under vacuum, and taken to the next step as it is.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:23][CH2:22]3)=[C:17]([CH2:24][C:25]3[CH:34]=[CH:33][C:28]4[O:29][CH2:30][CH2:31][O:32][C:27]=4[CH:26]=3)[CH:16]=2)[O:8][CH:7]([S:35][CH3:36])[C@H:6]1[O:37]C(=O)C)(=O)C.[OH-].[Li+]>CO.C1COCC1.O>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C@H:9]3[C@H:10]([OH:11])[C@@H:5]([OH:4])[C@H:6]([OH:37])[CH:7]([S:35][CH3:36])[O:8]3)=[CH:16][C:17]=2[CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH2:23][CH2:22]1
Reactant: CSC1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CSC1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Step-XI: To a stirred solution of acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methylsulfanyl-tetrahydro-pyran-3-yl ester (80 mg, 0.14 mmol) in methanol:THF:water (3:2:1 mixture, 6 ml) was added lithium hydroxide (9 mg, 0.4 mmol). After stirring for 2 h at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken in ethyl acetate (10 ml) and washed with brine (5 ml), brine containing 1 ml of 5% aqueous KHSO4 (5 ml), brine (5 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish 55 mg of (2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol. 1H NMR (400 MHz, CD3OD): δ 0.52-0.60 (m, 2H), 0.80-0.90 (m, 2H), 1.78-1.88 (m, 1H), 2.15 (s, 3H), 3.32-3.35 (m, 3H), 4.05 (q, J=15.2 Hz, 2H), 4.11 (d, J=8.8 Hz, 1H), 4.17 (s, 4H), 4.38 (d, J=10 Hz, 1H), 6.61 (d, J=8.0 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H). MS (ES) m/z 462.3 (M+18).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([NH:28][CH3:29])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3Cl)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:30])[CH:5]=1)(=[O:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([NH:28][CH3:29])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3[N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:30])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1
Reactant: C1COCCN1
Product: CNS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-chloro-N-methyl-benzenesulfonamide and morpholine (58%, light yellow solid, MS (m/e): 503.1 (M−H, 100%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:10]([O:14][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]/[CH:29]=[CH:28]\[CH2:27]/[CH:26]=[CH:25]\[CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCCCOS(C)(=O)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound VI-8 (210 mg, 43.7%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 124 mg, 0.644 mmol) and (11Z,14Z)-icos-11,14-dienyl methanesulfonate (Nu-Chek Prep, Inc; 600 mg, 1.61 mmol).
Reaction SMILES: [NH:1]([CH:8]1[CH2:17][CH:16]2[N:11]([CH2:12][CH2:13][C:14]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:15]=32)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:15]2[CH:16]3[N:11]([CH2:12][CH2:13][C:14]=2[CH:21]=1)[CH2:10][CH2:9][CH:8]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:33]([NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH2:17]3
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2c(cc1OC)C1CC(Nc3ccccc3)CCN1CC2
Product: COc1cc2c(cc1OC)C1CC(N(C(=O)Nc3ccccc3)c3ccccc3)CCN1CC2

Procedure:
By a procedure analogous to that of Example 1, 2-anilino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (U.S. Pat. No. 3,634,431) is reacted with phenyl isocyanate to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:57]=[CH:56][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:48][CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:42]1([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:32](=[O:33])[N:31]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[N:30]=[CH:29][CH:28]=4)=[O:26])=[CH:20][C:19]=3[F:41])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:57][CH:56]=3)[N:9]=2)[CH2:48][CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1
Reactant: COc1ccc(Cn2nc(N3CCCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(N3CCCNCC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-diazepane-1-carboxylate (118.3 mg, 0.1519 mmol), 2,2,2-trifluoroacetic acid (346.4 mg, 3.038 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for one hour. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (60.7 mg, 58.88%). LRMS (APCI pos): m/e 679 (M+1).
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9](=O)[CH:8]=1)[CH3:5])([OH:3])=[O:2].[NH:19]([C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:23][N:22]=1)[NH2:20]>Cl.C(O)(=O)C>[CH3:28][O:27][C:26]1[C:21]([N:19]=[N:20][C:9]2[CH:8]=[C:7]([O:6][CH:4]([C:1]([OH:3])=[O:2])[CH3:5])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[OH:17])=[N:22][CH:23]=[C:24]([S:29](=[O:32])(=[O:31])[NH2:30])[CH:25]=1
Reactant: CC(OC1=CC(=O)C(=O)c2ccccc21)C(=O)O
Reactant: COc1cc(S(N)(=O)=O)cnc1NN
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(S(N)(=O)=O)cnc1N=Nc1cc(OC(C)C(=O)O)c2ccccc2c1O
Reaction time: 8 h

Procedure:
4-(1-Carboxyethoxy)-1,2-naphthoquinone (0.22 g, 9×10-4) and 2-hydrazino-3-methoxy-5-sulfamoylpyridine (0.2 g, 9×10-4 mole) were added to acetic acid (15 ml), along with 2 to 3 drops of concentrated hydrochloric acid. After stirring overnight, the resulting precipitate was collected by filtration, air dried, slurried twice with boiling acetic acid (5 ml) and isolated again by filtration; yield, 80 mg (20 percent).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:36])([C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:35])[CH3:19])=[CH:13][C:12]=1[CH3:37])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Li+].[OH-]>>[CH3:37][C:12]1[CH:13]=[C:14]([O:17][C:18]([CH3:19])([C:20]2[S:24][C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)=[N:22][C:21]=2[CH3:35])[CH3:36])[CH:15]=[CH:16][C:11]=1[CH2:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:38])=[O:2]
Reactant: CCCCCC(Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCCCCC(Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-benzyl)-heptanoic acid methyl ester was treated with LiOH to obtain [rac]-2-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-benzyl)-heptanoic acid as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 86.3 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 21; 290 mg, 0.90 mmol) and iodomethane (0.15 mL, 2.3 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulfate), filtered, and evaporated to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (260 mg, 86%) as a yellow solid. ES(+)-MS (M+H) 335.
Reaction SMILES: C(CNCC(O[C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)=[C:22]([F:34])[CH:21]=2)[CH2:19][CH2:18]1)=[O:16])CNCC(=O)C)(=O)C.C([CH2:38][NH:39][CH2:40][CH:41]([O:65][C:66](=[O:68])[CH3:67])[CH2:42][NH:43][CH2:44][C:45]([C:47]1(C2C=CC(C3C=CC(Cl)=C(Cl)C=3)=C(F)C=2)CC1)=[O:46])(=O)C>CN(C1C=CN=CC=1)C>[C:45]([CH2:44][NH:43][CH2:42][CH:41]([O:65][C:66](=[O:68])[CH3:67])[CH2:40][N:39]([C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)=[C:22]([F:34])[CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:38])(=[O:46])[CH3:47]
Reactant: CC(=O)CNCC(CNCC(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1)OC(C)=O
Reactant: CC(=O)CNCC(CNCC(C)=O)OC(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Agent: CN(C)c1ccncc1
Product: CC(=O)CNCC(CN(C)C(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1)OC(C)=O

Procedure:
Note that although the procedure is similar to that utilized to synthesize C4 (second method, see Example 5), with the exception that also DMAP was added in the coupling step of Example 5 but not of Example 6, the isolated product is different, being acetic acid 1-[(acetylmethylamino)methyl]-2-{[1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarbonyl]methylamino}ethyl ester in Example 6 and 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid 2-acetylmethylamino-1-(acetylmethylaminomethyl)ethyl ester in Example 5.