Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[Mg].[CH:9]([C@@H:11]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][C@@H:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10].[NH4+].[Cl-]>C1COCC1>[OH:10][C@H:9]([C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1)[C@@H:11]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][C@@H:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(Br)s1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc([C@@H](O)[C@H]2[C@@H](c3ccccc3)CC(=O)N2C)s1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A portion (1 mL) of a solution of 2-bromo-5-methylthiophene (0.56 mL, 5.5 mmol) in THF (20 mL) was added to Mg turnings (135 mg, 5.5 mmol). The mixture was gently heated until the magnesium started to be consumed. The remaining thiophene solution was added in 1 mL increments to maintain a constant gentle reflux. After the addition was complete, the solution was heated at the reflux temperature for 3 min, then was allowed to cool to room temperature. To a −78° C. solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 190 mg, 1 mmol) in THF (7.5 mL) was slowly added the freshly prepared Grignard reagent and the reaction mixture was allowed to warm to room temperature. After 2 h a saturated NH4Cl solution was added and the mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (100% EtOAc) to give (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-methyl(2-thienyl))methyl]-1-methyl-4-phenylpyrrolidin-2-one (156 mg, 52%) as a white powder: mp 185-188° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([O:17]C)=[O:16])[N:11]([CH3:19])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>CS(C)=O>[F:1][C:2]1[C:3]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[N:11]([CH3:19])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1c(C)c(-c2ncc(Cl)cc2F)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1c(-c2ncc(Cl)cc2F)nn(C)c1C(=O)O
Temperature: 22 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
6.75 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-methyl-5methoxycarbonyl-1-methyl-[1H]-pyrazole are suspended in 40 ml of dimethyl sulfoxide. 14.3 ml of a 2 molar sodium hydroxide solution are added dropwise, while cooling occasionally in an ice-bath (temperature <30° C.). The thick yellow-brown suspension is stirred at 22° C. for 2 hours. The resulting suspension is then introduced into ice-water and the pH is brought to 1 with 2 molar hydrochloric acid. The slurry formed is filtered with suction and the solid is washed thoroughly with cold water and then dried in vacuo at 60° C. 5.97 g of the desired title compound are obtained as a beige solid of melting point 194-196° C.
Reaction SMILES: Br.C(OC([NH:12][C@H:13]([C:17]1[O:18][C:19]([C:26]2[C:34]3[C:29](=[C:30]([Br:35])[CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=1)[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1.CC(OC)(C)C>C(O)(=O)C>[BrH:35].[NH2:12][C@H:13]([C:17]1[O:18][C:19]([C:26]2[C:34]3[C:29](=[C:30]([Br:35])[CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1nc([C@@H](NC(=O)OCc2ccccc2)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Agent: Br
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: COC(=O)c1nc([C@@H](N)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Reaction time: 0.33 h
Yield: 153.1 %

Procedure:
To 33% HBr in acetic acid (1.33 L) was added the title compound of Example 5 (403.4 g, 766 mmol) and the stirred vigorously for 1 hour and 20 min. The mixture was slowly and carefully added to MTBE (12 L) with external cooling and strong agitation. The mixture was stirred for 1 hour at 0° C. and filtered under N2. The hygroscopic solids were washed with MTBE (1 L) and dried to constant mass in a vacuum oven to yield the title compound (277.5 g, 76.5%) as a fine brown solid. 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH2:10][CH2:11][CH:12]=[CH:13][CH:14]=[CH:15][CH3:16])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Cl>C1COCC1>[OH:3][CH:4]([CH2:10][CH2:11][CH:12]=[CH:13][CH:14]=[CH:15][CH3:16])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CC=CC=CCCC(=O)CC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC=CC=CCCC(O)CC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
In a stream of nitrogen, sodium borohydride (5.1 g, 0.14 mol) and THF (360 ml) were put into a 1-L flask, followed by cooling to 0° C. Methyl 3-oxo-6,8-decadienoate (f) (88.8 g, 0.45 mol) was added dropwise thereinto for 1 hour. After completion of the dropwise addition, a 35% aqueous solution of hydrochloric acid (47 g) was added dropwise thereinto, followed by extraction twice with ethyl acetate (180 ml). After the organic layer was washed with water (178 mL), the solvent was removed under a reduced pressure. Thus, methyl 3-hydroxy-6,8-decadienoate (g) was obtained (86.1 g, 0.43 mol, yield 96%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.S(=O)(=O)(O)O.[OH-].[Na+]>OCC(CO)O>[F:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:15][CH:14]=[CH:19]2
Reactant: Nc1ccc(F)cc1Br
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: Fc1cc(Br)c2ncccc2c1
Temperature: 150 °C
Yield: 416.7 %

Procedure:
To a mixture of 7.0 g of 2-bromo-4-fluoro-aniline, 7.0 g of glycerol and 13.0 g of m-nitrobenzene sulfonic acid sodium salt, 20 ml of 70% sulfuric acid was added drop by drop. The reaction temperature was raised to 150° C. for 4 hr. The mixture was cooled, poured on water neutralized with NaOH and the formed precipitate was filtered to yield 34.7 g of 6-fluoro-8-bromo-quinoline. MS (ES) m/z (relative intensity): 227 (M++H, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.C1COCC1.Cl>CCCCCCC.C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:17])([CH3:16])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)(C)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)NCC(C)(C)C(=O)O
Temperature: 64 °C
Yield: 160.5 %

Procedure:
Two 22 L flasks were each charged with compound 54a (583 g, 2.38 mol), LiOH.H2O (204.5 g, 4.87 mol), THF (5.7 L), and water (4.75 L). The reaction mixtures were heated to 64° C. for 19 h. The mixtures were then cooled to 10° C. with an ice bath. Approximately 1 L of 6N HCl was added to each reaction mixture to bring the pH to 3-3.5. Each mixture was combined with 2.9 L of CH2Cl2, and the aqueous layers were separated. The aqueous layers were extracted with another 1.5 L portion of CH2Cl2. The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a white solid. The solid was slurried in 5 L of heptane for 1 h, filtered, and vacuum dried to give 830 g (80% yield) of compound 55 as a white solid, mp 114-116° C. Anal. Calcd for C10H19NO4: C, 55.28; H, 8.81; N, 6.45. Found: C, 55.55; H, 8.77; N, 6.56.
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]([CH:20]=[O:21])[CH:7]=2)[CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[C@H:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([CH2:20][OH:21])[CH:7]=2)[CH2:2]1
Reactant: O=Cc1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To an ice-cooled solution of (2S)-1,2-epoxy-3-(3-formyl-4-benzyloxyphenoxy)propane (2.6 g) in methanol (30 ml) was added sodium borohydride (381 mg). The mixture was stirred at the same temperature for 1 hour and partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give (2S)-1,2-epoxy-3-(3-hydroxymethyl-4-benzyloxyphenoxy)propane (2.57 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.CCOC(C)=O>[N:42]([CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([NH:12][C:13]2[N:18]=[C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)[C:16]3=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]3[N:14]=2)[CH:4]=[C:5]([C:10]#[N:11])[CH:6]=1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc(CO)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cc(CN=[N+]=[N-])c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Temperature: 70 °C
Yield: 62.6 %

Procedure:
A mixture of 2-((2-chloro-5-cyano-3-(hydroxymethyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 402)(120 mg, 0.315 mmol), diphenylphosphoryl azide (0.102 mL, 0.473 mmol) and DBU (0.071 mL, 0.473 mmol) in dry dioxane (3 mL) was heated at 70° C. for 20 hr. It was diluted with EtOAc and washed with water. The aqueous phase was washed with EtOAc and the combined organic phases were washed with brine and dried with sodium sulfate. Removal of the solvents followed by radial silica gel chromatography eluting with DCM containing 0 to 3% MeOH afforded 2-((3-(azidomethyl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:8]=[C:9](Br)[C:10]=1[OH:11])=[O:4].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(Br)c1O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccc2)c1O
Temperature: 80 °C
Reaction time: 10 h
Yield: 70.5 %

Procedure:
To a solution of 5-Bromo-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methylester (0.3 g, 0.8 mmol) in toluene (5 mL) was added phenylboronic acid (0.19 g, 1.6 mmol), tetrakistriphenylphosphine (0.0.09 g, 0.08 mmol), Na2CO3(2.4 ml, 1N solution) and stirred the reaction mixture at 80° C. for 10 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography (20:80 EtOAc:hexane) gave pure 4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (0.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][C:22]([F:21])([F:32])[F:33])[CH:25]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1cccc(OC(F)(F)F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (145 mg, 0.41 mmol) and 3-(trifluoromethoxy)benzylamine (53 mg, 0.39 mmol). The title compound was obtained as a solid (55 mg, 26% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.45 (1H, m), 8.98 (2H, m), 8.47 (1H, s), 7.48 (2H, m), 7.30 (2H, m), 4.45 (2H, m). MS m/z: 522.09, 524.08 [M+H]+.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH2:31]([NH:38][C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2c(NCc3ccccc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (140 mg, 0.29 mmol) was dissolved in dry pyridine (2 mL) and benzylamine (500 μL, excess) was added to it and the reaction mixture was stirred at 80° C. for 1 hour. Solvent was distilled and the crude product was purified over silica gel column to afford the title compound as light yellow solid (112 mg, 83%); 1H NMR (300 MHz, CDCl3) δ: 9.27 (b, 1H, NH), 7.39-7.32 (m, 5Hs, Ar Hs), 6.96 (s, 2H, benzoyl Hs), 6.61 (d, 1H, J=8.47 Hz), 6.50 (d, 1H, J=8.10 Hz), 4.83 (d, 2H, J=4.95 Hz, Benzyl Hs), 3.91 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[O:20][C:21]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=3)=[C:22]([C:24]([O:26]CC)=[O:25])[N:23]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].O.[OH-].[Li+].Cl.C(OCC)(=O)C>CO.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[O:20][C:21]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:31]=3)=[C:22]([C:24]([OH:26])=[O:25])[N:23]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N[C@H]2C[C@@H](CC)N(C(=O)OCC)c3ccc(OC)nc32)oc1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)o2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(4-ethoxycarbonyloxazol-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) and lithium hydroxide monohydrate (78 mg) are dissolved in a mixture of methanol (3 ml) and water (500 μl), and the mixture is stirred at room temperature for 2 hours. The reaction solution is acidified by adding 2N aqueous HCl solution, then added ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-carboxyoxazol-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (190 mg). MS (m/z): 617 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:56])([CH3:55])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:54])([C@@:17]4([CH3:53])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][C@@H:43]5[CH2:45][C@H:40]2[CH2:41][N:42]5C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]>C(Cl)Cl>[C@H:40]12[CH2:45][C@H:43]([NH:42][CH2:41]1)[CH2:44][N:39]2[CH2:38][CH2:37][NH:36][C@:20]12[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:53])([CH2:18][CH2:19]2)[C@@:16]2([CH3:54])[C@@H:25]([C@:26]3([CH3:29])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:55])([CH3:56])[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:28][CH2:27]3)[CH2:24][CH2:23]1.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,4S)-tert-butyl 5-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (419 mg, 0.545 mmol) in DCM (10 mL) was added TFA (2 mL, 26.0 mmol) and the mixture was stirred at rt for 3 h. The reaction mixture was concentrated and dark brown viscous oil was dried to remove all TFA. The material was purified by reverse phase HPLC using HPLC method 6 and dried under vacuum to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate, 3 TFA (75.2 mg, 12.28% yield) as a light brown solid. LC/MS: m/e 668.7 (M+H)+, 2.36 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.77 (br. s., 1H), 9.49 (br. s., 1H), 7.92 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 5.28 (d, J=4.4 Hz, 1H), 4.76 (br. s., 1H), 4.69 (br. s., 1H), 4.31 (br. s., 1H), 3.96 (br. s., 1H), 3.90 (s, 3H), 3.66 (br. s., 1H), 3.40-3.10 (m, 5H), 3.09-2.89 (m, 2H), 2.81 (br. s., 1H), 2.23-2.06 (m, 4H), 2.05-1.91 (m, 3H), 1.85 (br. s., 1H), 1.78-1.73 (m, 1H), 1.69 (br. s., 3H), 1.65 (br. s., 1H), 1.62-1.30 (m, 11H), 1.26-1.17 (m, 2H), 1.11 (br. s., 3H), 1.05 (br. s., 3H), 0.99 (br. s., 3H), 0.93 (br. s., 6H). 13C NMR (101 MHz, CHLOROFORM-d) 167.2, 148.5, 147.1, 146.2, 130.0, 128.5, 127.9, 123.8, 114.8, 111.6, 77.24-77.18, 71.3, 65.8, 60.9, 57.7, 54.4, 52.7, 52.0, 49.2, 48.7, 48.62-48.49, 46.3, 45.0, 42.0, 41.6, 40.6, 37.4, 37.0, 36.2, 33.6, 32.5, 29.4, 28.0, 27.3, 25.8, 25.0, 20.9, 20.8, 19.5, 19.1, 16.3, 15.9, 15.2, 14.4.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[B-](F)(F)(F)[CH:12]=[CH2:13].[K+].C(N(CC)CC)C>C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:8]([C:7]1[C:2]([CH:12]=[CH2:13])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C=C[B-](F)(F)F
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 52.8 %

Procedure:
A solution of 2-chloro-3-nitropyridine (0.20 g, 1.261 mmol), potassium trifluoro(vinyl)borate (0.203 g, 1.514 mmol) and PdCl2(dppf) (0.018 g, 0.025 mmol) dissolved in isopropanol (4 mL) and triethylamine (0.211 mL, 1.514 mmol) was gently purged with stream of nitrogen for a few minutes then heated at 100° C. for 4 h. The reaction was cooled and filtered through CELITE® and the solvent was removed under vacuum. The resulting residue was purified via automated flash chromatography (40 gram silica gel, hex/ethyl acetate). Fractions containing the desired product were collected, combined, and evaporated in vacuo to afford tan oil as final product, 3-nitro-2-vinylpyridine (100 mg, 0.666 mmol, 52.8% yield). HPLC RT (Method N)=1.75 minutes.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:39])[C:36]([OH:38])=O)=[CH:31][CH:30]=1>>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]([N:13]3[CH2:14][CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH:16]([N:18]([CH3:19])[C:36](=[O:38])[CH:35]([C:32]4[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=4)[CH3:39])[CH2:17]3)=[O:12])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CC(C(=O)N(C)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-propionamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-fluoro-alpha-methylphenyl acetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless oil. MS m/e: 560.2 [M]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C)C=O.[F:12][C:13]([F:20])([F:19])[CH2:14]CC(O)=O>CCCCC>[F:12][C:13]([F:20])([F:19])[CH2:14][CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(O)CCC(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(F)(F)F
Yield: 76 %

Procedure:
101 ml of oxalyl chloride and 0.1 ml of dimethylformamide was added to a solution of thus obtained 131 g of the 4,4,4-trifluorobutyric acid in 1 liter of pentane, and the resultant solution was refluxed for three hours. Then the reaction solution was distilled to yield 112 g of 4,4,4-trifluorobutyryl chloride in a yield of 76%. (b.p. 103° C./760 mmHg)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][O:21][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
360 mg (1.07 mmol) 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol in 3 ml CH2Cl2 were treated with 100 μl (1.29 mmol) methanesulfonic acid chloride and 450 μl (3.23 mmol) triethylamine at 0° C. The solution was stirred at RT for 2 h, diluted with CH2Cl2 and washed with 1N HCl and dried over Na2SO4. Evaporation gave 350 mg (79%) crude Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester, which was directly subjected to the following reaction.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][NH:20][CH3:21].C(N(CC)CC)C>C(O)CCC>[CH3:19][N:20]([CH3:21])[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CNC
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CN(C)c1ncnc2[nH]cc(-c3cccc(C#N)c3)c12
Temperature: 150 °C

Procedure:
A mixture of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (157 mg, 0.616 mmol), dimethylamine (189 mg, 4.19 mmol) and triethylamine (182 mg, 1.80 mmol) in n-butanol (12 mL) was heated under microwave irradiation at 150° C. for 25 minutes. After concentration in vacuo, the residue was purified by preparative HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: ammonia in water, pH 10; Mobile phase B: acetonitrile; Gradient: 25% to 65% B) to give the product as a white solid. Yield: 72.1 mg, 0.274 mmol, 44%. LCMS m/z 263.8 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.15 (br s, 1H), 8.28 (s, 1H), 7.93 (br s, 1H), 7.78 (br d, J=7.8 Hz, 1H), 7.73 (br d, J=7.8 Hz, 1H), 7.62 (br dd, J=8.0, 7.8 Hz, 1H), 7.57 (br s, 1H), 2.73 (s, 6H).