Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([C:12]([O:14]CC)=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1>C(O)C>[CH2:10]([O:9][C:7]([C:3]1([C:12]([OH:14])=[O:13])[CH2:4][CH2:5][CH2:6]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydroxide (1N, 22.5 mmol) was added dropwise (1 drop for every 20 second) to a stirred solution of diethyl 1,1-cyclobutanedicarboxylate (4.5 g, 22.5 mmol) in ethanol (20 ml). The resulting mixture was stirred at room temperature for 6 hours, then concentrated by evaporation to a volume of about 10 ml. This residue was shaked with diethyl ether and the aqueous layer was separated. This aqueous was acidified with 12N hydrochloric acid while the temperature was kept below 10° C. The resulting mixture was extracted with diethyl ether (3×50 ml). The combined extracts were dried over magnesium sulfate, filtered and evaporated to yield the desired product as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]1=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][C:19]2=[O:27])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1Cc2ccccc2N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C2C(=O)Nc3ccccc32)cc(C(C)(C)C)c1O
Yield: 43.2 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5.28 g; 22.5 mmol), 2-oxindole (3.0 g; 22.5 mmol), and p-toluene sulfonic acid (0.25 g) in toluene (100 ml) is heated under reflux for 18 hours. The reaction mixture is cooled and filtered. The residue is washed with ether and dried @80° C. under vacuum for 18 hours to give 3.4 g (43.2%) of a yellow solid, mp 224°-225° C. (lit. mp 227° C.*).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH2:25]([NH:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31])[CH:26]([CH3:28])[CH3:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:35]4[CH:36]=[CH:37][C:32]([C:30]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:31])=[CH:33][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CC(C)CNC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)CNC(=O)c1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Temperature: 120 °C
Yield: 5.1 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(isobutylcarbamoyl)-phenyl-boronic acid (23 mg, 0.1 mmol). The mixture was heated at 120° C. in a microwave reactor for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-isobutylbenzamide (1.28 mg, 5%). 1H-NMR (MeOD): 0.96 (d, 6H), 1.94 (m, 1H), 2.15 (d, 1H), 2.47 (t, 1H), 3.29 (s, 3H), 3.31 (s, 1H), 3.32 (s, 1H), 5.30 (d, 1H), 7.06 (t, 2H), 7.33 (m, 1H), 7.42 (t, 2H), 7.48 (d, 3H), 7.53 (d, 1H), 7.66 (d, 1H), 7.72 (d, 1H), 7.91 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]1([CH2:67][C:68](O)=[O:69])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:68](=[O:69])[CH2:67][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 43.1 %

Procedure:
DIPEA (68 mg, 0.53 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (76 mg, 0.18 mmol) in DMF (1 mL). HOBT (24 mg, 0.18 mmol) and EDCI.HCl (34 mg, 0.18 mmol) were then added at room temperature. After 2 minutes, phenyl acetic acid (20 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. the resulting residue was purified by column chromatography (using silica gel 60-120 mesh and 1% methanol in chloroform as eluent) to afford 28 mg (43.7% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-2-phenyl-acetamide. LCMS Purity: 94.1%, 1H NMR (CDCl3): δ 7.8-7.7 (d, 1H). 7.6 (m, 2H), 7.4-7.2 (m, 5H), 6.5 (bd, 1H), 4.1 (m, 1H), 4.0 (m, 2H), 3.8 (m, 1H), 3.8-3.4 (m, 6H), 3.3 (t, 1H), 3.2-3.1 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)(=[O:4])=[O:3].[BH4-].[Na+].Cl>CCO>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C=O)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(CO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-methanesulfonyl-2-trifluoromethyl-benzaldehyde (49.2 g, 0.20 mol) in dry EtOH (500 ml), cooled in an ice-bath, is added sodium borohydride (10.8 g, 0.22 mol), portionwise over 30 mins. The reaction mixture is allowed to warm up slowly to room temperature then stirring is continued for 16 h. The reaction mixture is poured into a beaker of crushed ice (700 ml) and adjusted to pH 1 with 2N HCl (approx. 200 ml). The resulting pale yellow suspension is extracted with CH2Cl2 (3×150 ml), dried (MgSO4) and evaporated to dryness in vacuo. to afford a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:14])[C:3]=1[CH3:15].[F:16][C:17]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:18]=1[NH2:19].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:16][C:17]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:14])[C:3]=1[CH3:15]
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1c(Cl)c(C(=O)O)c2n(c1=O)CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)c2n(c1=O)CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.1 %

Procedure:
Compound 8d (183 mg, 1.04 mmol) and 2-fluoro-4-iodoaniline (384 mg, 1.62 mmol) stirred in dry THF (8 ml) at 0° C. under nitrogen. LiHMDS (1M in THF, 2.4 mL, 2.4 mmol) was added dropwise, and the reaction stirred 4 h while warming to RT. The solution was quenched with 1N HCl and extracted with 10% MeOH/CH2Cl2 (3×). Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (10% to 20% MeOH/CH2Cl2) gave 76 mg (22%) of compound 8e as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ7.57 (d, 1H, J=9.1 Hz), 7.37 (d, 1H, J=8.3 Hz), 6.38 (t, 1H, J=9.0 Hz), 4.00 (t, 2H, J=7.6 Hz), 3.41 (t, 2H, J=8.1 Hz), 2.06-2.09 (m, 2H), 1.61 (s, 3H). MS (ES) [m+H] calc'd for C16H14FIN2O3, 429. found 429.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=O>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: Cc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a solution of the crude product of 4-fluorothiobenzamide (2.0 g, 12.9 mmol) in EtOH (30 ml) is added 2-bromo-4' methylacetophenone (2.75 g, 12.9 mmol). The mixture is heated to reflux for 24 hours. The course of the reaction is followed by thin layer chromatography. Upon completion of the reaction the solution is cooled to room temperature and the white precipitate filtered and dried under vacuum to yield 2-(4'-fluorophenyl)-4-(p-tolyl) thiazole (1.54 g, 54%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:18])[C@@H:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[N:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:19][CH2:20][C:21](=O)[CH2:22][CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([CH:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:18])[C@@H:13]([NH:17][CH:21]([CH2:22][CH3:23])[CH2:20][CH3:19])[CH2:14][CH2:15][CH3:16])=[N:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(=O)CC
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(CC)CC)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NC(CC)CC)C(=O)Nc1ncc(C(CC)CC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid [5-(1-ethyl-propyl)-thiazol-2-yl]-amide (107 mg, 0.4 mmol) and 3-pentanone (34 mg, 0.4 mmol)in 3 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (131 mg, 0.62 mmol) and stirred at room temperature overnight. An additional sodium triacetoxyborohydride (167 mg)was added and the resulting mixture was stirred at room temperature for 4 hrs. The mixture was quenched with ammonium hydroxide/water and extracted with methylene chloride. The organic layer was separated, dried, filtered and concentrated to dryness to give a yellow oil. The oil was purified by Shimadzu HPLC to give 2-(S)-(1-Ethyl-propylamino)-pentanoic acid [5-(1-ethyl-propyl)-thiazol-2-yl]-amide as a colorless oil, RT=1.88 min, M+1=340.4.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:31][C:32]1[C:36]([C:37]2[CH:38]=[C:39]([S:47]([NH:50][CH:51]3[CH2:55][CH2:54][CH2:53][CH:52]3[C:56](O)=[O:57])(=[O:49])=[O:48])[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=2)=[C:35]([CH3:59])[O:34][N:33]=1.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:25]1([NH:30][C:56]([C@H:52]2[CH2:53][CH2:54][CH2:55][C@H:51]2[NH:50][S:47]([C:39]2[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[C:37]([C:36]3[C:32]([CH3:31])=[N:33][O:34][C:35]=3[CH3:59])[CH:38]=2)(=[O:49])=[O:48])=[O:57])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2C(=O)O)c2cccnc2c1
Reactant: NC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)N[C@@H]2CCC[C@@H]2C(=O)NC2CCCC2)c2cccnc2c1

Procedure:
To a mixture of HATU (38 mg, 0.10 mmol), cyclopentanamine (9 mg, 0.10 mmol), and 1S,2R)-2-(7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamido)cyclopentanecarboxylic acid (21 mg, 0.05 mmol) in anhydrous DMF (1 mL), was added slowly Hunig's base (30 uL, 0.16 mmol) with stirring until the starting material acid disappeared (about 1 hr). The reaction mixture was acidified with aqueous citric acid to pH 2-3, then subjected to preparative HPLC to give (1S,2R)—N-cyclopentyl-2-(7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamido)cyclopentanecarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:50])([CH3:49])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:48])([C@@:18]4([CH3:47])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:50])([CH3:49])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:48])([C@@:18]4([CH3:47])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 34869.6 %

Procedure:
To a solution of methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-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 (16 mg, 0.023 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.25 mL, 0.250 mmol). The mixture was heated to 60° C. overnight for 15.25 h then was cooled to rt. The mixture was directly loaded onto the prep HPLC for purification. The fractions containing the expected product were combined and concentrated under reduced pressure to give 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-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)benzoic acid (6 mg, 8.02 mmol, 34.5% yield) as a clear, colorless film. LCMS: m/e 673.5 (M+H)+, 1.75 min (method 2). 1H NMR (500 MHz, Acetic acid d4) δ 7.96 (t, J=7.9 Hz, 1H), 7.09 (dd, J=7.9, 1.2 Hz, 1H), 7.03 (d, J=11.9 Hz, 1H), 5.42 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.58-3.40 (m, 4H), 3.26-3.16 (m, 2H), 2.94-2.85 (m, 1H), 2.56-2.48 (m, 2H), 1.76 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 2.29-0.85 (m, 26H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:17]([CH:18]=[N:19][C:20]=2[C:23]([OH:25])=[O:24])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[CH2:14]1)=[O:12])=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:17]([CH:18]=[N:19][C:20]=2[C:23]([OH:25])=[O:24])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (R)-5-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid (35 mg, 0.06 mmol) in dry DCM (5 mL), was added trifluoroacetic acid (6.18 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid was crystallised from hexane to afford trifluoroacetic acid salt of 5-[(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid (28 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:9][C:7]1[C:6]([O:10][CH3:11])=[CH:5][C:3]([NH2:4])=[C:2]([CH:12]2[CH2:14][CH2:13]2)[CH:8]=1
Reactant: COc1cc(N)c(Br)cc1Cl
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(N)c(C2CC2)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of Example 18A (1.0 equivalents), cyclopropyl boronic acid (1.1 equivalents), tricyclohexylphosphine (0.05 equivalents), palladium acetate (0.025 equivalents) and K3PO4 (2 equivalents) in a 20:1 volume ratio of toluene and water was sparged with nitrogen for 15 minutes. The reaction mixture was then heated to 100° C. for 12 hours, cooled, diluted with water, stirred for 1 hour and filtered through a diatomaceous earth pad, and the pad was rinsed with toluene. The filtrate was mixed and the layers were separated. The organic layer was washed with water and saturated brine, dried (Na2SO4), filtered and concentrated to an oil that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[N:4]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.Cl.[NH2:21][CH2:22][CH:23]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[C:31]=1[F:38])[CH2:24][C:25](OCC)=[O:26].FC1C(F)=CC(F)=CC=1C=CC(OCC)=O.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.[N+](C)([O-])=O>[CH3:1][C:2]1[C:6]([CH2:7][N:21]2[CH2:22][CH:23]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[C:31]=3[F:38])[CH2:24][C:25]2=[O:26])=[C:5]([CH3:9])[N:4]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: CCOC(=O)CC(CN)c1cc(F)cc(F)c1F
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c(C=O)c2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)C=Cc1cc(F)cc(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2nc(C)c(CN3CC(c4cc(F)cc(F)c4F)CC3=O)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
In a 100 ml three-necked flask fitted with a magnetic stirrer, under inert atmosphere, 3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x56 (0.87 g, 3.1 mmol) and ethyl 4-amino-3-(2,3,5-trifluorophenyl)butanoate hydrochloride x60 (synthesized from nitromethane and ethyl 3-(2,3,5-trifluorophenyl)acrylate by the same methodology as described in Kenda et al., J. Med. Chem. (2004), 47, 530-49; 0.94 g, 3.1 mmol) are dissolved in CH2Cl2 (30 ml). Triethylamine (0.86 ml, 6.3 mmol) and NaBH(OAc)3 (1.33 g, 6.3 mmol) are added and the heterogeneous mixture became a solution. After 16 h at room temperature, two additional portions of NaBH(OAc)3 are added (1.6 mmol after 16 h and 3.2 mmol after 48 h) and 1.6 mmol of triethylamine are added after 24 h stirring at room temperature. The reaction is quenched with water and the aqueous phase is extracted three times with diethylether. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by column chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 95/4.5/0.5 (v/v/v)) to afford 0.83 g of 1-({3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one x61.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[CH2:33]O)[O:29][CH2:28][CH:27]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26]2.O>C(#N)C>[Br:20][CH2:33][C:32]1[CH:31]=[C:30]2[C:25]([CH2:26][CH:27]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:28][O:29]2)=[CH:24][C:23]=1[F:22]
Reactant: CCCCCC1COc2cc(CO)c(F)cc2C1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCCCCC1COc2cc(CBr)c(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.2 g (38.9 mmol) of triphenylphosphine are suspended in 80 ml of acetonitrile, and 2.0 ml (39.0 mmol) of bromine are added dropwise with ice cooling. A solution of 10.0 g (38.4 mmol) of (6-fluoro-3-pentylchroman-7-yl)methanol in 20 ml of acetonitrile is subsequently added, and the mixture is stirred overnight at room temp. After addition of water, the mixture is extracted three times with n-heptane, and the combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with heptane/toluene (4:1), giving 7-bromomethyl-6-fluoro-3-pentylchroman as a colourless oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:7]([O:21][CH3:22])[CH:6]=1)([OH:4])[CH3:3].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl.C(N(CC)CC)C>[CH3:3][C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:23](=[O:25])[CH3:24])=[C:7]([O:21][CH3:22])[CH:6]=1)([OH:4])[CH3:1]
Reactant: COc1cc(C(C)(C)O)ccc1NS(=O)(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)O)ccc1N(C(C)=O)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-1-(4-phenylsulfonylamino-3-methoxyphenyl)ethanol (2.65 g; prepared in Reference Example 38.) in methylene chloride (15 ml), acetic anhydride (3.05 ml) and triethylamine (4.60 ml) were added. The mixture was stirred overnight at room temperature. The solvent was distilled off. The residue was purified on silica gel column chromatography (hexane:AcOEt=3 4) to give the title compound (2.33 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[F:18].CI.[CH3:21]CC([O-])(C)C.[K+]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:21])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[F:18]
Reactant: O=C1c2cc(Br)c(F)cc2CC12CCC(O)CC2
Reactant: CCC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=O
Temperature: 35 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of 6′-bromo-5′-fluoro-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 7, 1.94 g, 6.19 mmol) and methyl iodide (9.65 ml, 154 mmol) in 2-Me THF (80 mL) was heated to 35° C. Potassium tert-pentoxide (1.7 M in toluene) (5.01 g, 9.91 mmol) was slowly added dropwise over 10 min and the resulting mixture was stirred at 35° C. for 1 h. The reaction mixture was cooled to r.t., and partitioned between water and EtOAC. The organic phase was dried over magnesium sulfate and concentrated, to give the title compound (2.0 g, 99% yield). The product was used in the next step. MS (EI) m/z 326, 328 M+.