Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.FC1C=C(CN[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(O)=O)=CC=3)=CC4)CC2)C=CN=1.[F:88][C:89]1[CH:90]=[CH:91][C:92]([CH:95]=O)=[N:93][CH:94]=1>>[F:88][C:89]1[CH:90]=[CH:91][C:92]([CH2:95][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[N:93][CH:94]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)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
Reactant: O=Cc1ccc(F)cn1
Agent: C=C(C)[C@@H]1CC[C@]2(NCc3ccnc(F)c3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ccc(F)cn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 47 %

Procedure:
The title compound was prepared in 47% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-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 following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-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)benzoic acid, except 5-fluoro-2-formylpyridine was used instead of 2-fluoropyridine-4-carboxaldehyde in Step 1. LCMS: m/e 639.5 (M+H)+, 3.33 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=8.46 (d, J=2.7 Hz, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.68 (dt, J=2.7, 8.2 Hz, 1H), 7.53 (dd, J=4.1, 8.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.31 (dd, J=1.7, 6.3 Hz, 1H), 4.83 (s, 1H), 4.74 (s, 1H), 4.49 (d, J=15.3 Hz, 1H), 4.32 (d, J=15.0 Hz, 1H), 2.78 (dt, J=5.3, 10.9 Hz, 1H), 2.22-2.06 (m, 5H), 1.96 (dt, J=3.4, 12.2 Hz, 1H), 1.89-1.82 (m, 1H), 1.80 (d, J=10.7 Hz, 2H), 1.76 (s, 3H), 1.74-1.66 (m, 2H), 1.64-1.54 (m, 4H), 1.53-1.47 (m, 2H), 1.46-1.42 (m, 1H), 1.41-1.37 (m, 1H), 1.33 (s, 3H), 1.29 (dd, J=3.8, 9.9 Hz, 1H), 1.24 (dd, J=4.1, 13.0 Hz, 1H), 1.13 (s, 3H), 1.07 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: C(OCC)C.[CH3:6][C:7]1([CH3:14])[O:12][CH2:11][C:10](=[O:13])[CH2:9][O:8]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:6][C:7]1([CH3:14])[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]1
Reactant: CC1(C)OCC(=O)CO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)OCC(O)CO1
Yield: 93.4 %

Procedure:
To a diethyl ether (150 ml) solution of 2,2-dimethyl-1,3-dioxan-5-one (15 g, 0.115 mol), lithium aluminum hydride (4.38 g, 0.115 mol) was added at 0 to 8° C. for one hour in a nitrogen atmosphere. To the reaction mixture, water (4.2 ml), a 5N aqueous sodium hydroxide solution (4.2 ml), and water (12.8 ml) were sequentially added dropwise at 0 to 10° C. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (14.2 g, 93.4%) as a colorless oil.
Reaction SMILES: [S:1]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=O)[CH2:3][CH2:2]1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1>CCO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[NH:21][C:4]1[C:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=3[S:1][CH2:2][C:3]2=1
Reactant: O=C1CCSc2ncccc21
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CSc1ncccc1-3

Procedure:
A mixture of 2,3-dihydro-thiopyrano[2,3-b]pyridin-4-one (2.24 g, 13.6 mmoL) and 4-methoxy-phenylhydrazine HCl salt (2.60 g, 14.9 mmoL) in EtOH (10 mL) was refluxed for 5 hours. The reaction mixture was cooled and filtrated through a pad of Celite to remove any solids in the mixture. The solvent was removed in vacuo. The remaining residue was partitioned between EtOAc and saturated NaHCO3. The aqueous phase was extracted two times with EtOAc. The organic layer of each extraction was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc1:1 as eluent) to yield the title compound as a pale solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C@H:10]([CH3:23])[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[CH2:1]([O:8][C:9](=[O:24])[C@H:10]([CH3:23])[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)c1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@H](NC(=O)c1cccc(N)c1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of N-(3-nitrobenzoyl)-L-alanine benzyl ester (5.0 g, 15.2 mmol) and ammonium chloride (8.2 g, 0.152 mol) in 90% aqueous ethanol (150 ml) was added portionwise iron powder (4.25 g, 76.1 mmol) under refluxing and stirring, which were continued for an additional 1 hour. The mixture was hot-filtered through Celite® (Johns Manville) and washed with hot aqueous ethanol. The filtrate was evaporated in vacuo to give a residue, which was extracted with ethyl acetate and the organic extract was washed with brine twice. After drying over MgSO4, the solvent was removed in vacuo to afford a viscous oil, which was crystallized soon on standing to give N-(3-aminobenzoyl)-L-alanine benzyl ester (4.5 g, 99.2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.O.[NH2:36][NH2:37]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:36][NH2:37])=[O:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CC(C)(Cc1nc(-c2cccc(Cl)c2)no1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Cc1nc(-c2cccc(Cl)c2)no1)C(=O)NN
Reaction time: 1 h
Yield: 81.8 %

Procedure:
3,3-Dimethyl-dihydro-furan-2,5-dione (6.4 g) was heated at 50° C. in ethanol (150 mL) overnight. The solvent was removed in vacuo and the residue triturated with hexane to yield 2,2-Dimethyl-succinic acid 4-ethyl ester (4.66 g) which was used without further purification. t-Butanol (7.5 mL) was added to a mixture of 2,2-Dimethyl-succinic acid 4-ethyl ester (2.74 g, 15.7 mmol) in dichloromethane (62 mL) containing magnesium sulfate (7.5 g) and conc. sulfuric acid (0.85 mL) and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the product was extracted into dichloromethane, washed with brine solution, dried and concentrated to yield the diested as a colorloess oil (1.89 g). The ethyl ester was hydrolyzed by trating the crude sample with potassium hydroxide (2.75 g) in a mixture of ethanol (50 mL) and water (25 mL) at room temperatire for 2 h. The reaction was acidified using 1N HCl (aq) and extracted into ether, dried and concentrated to yield 2,2-Dimethyl-succinic acid 1-tert-butyl ester (1.4 g). This acid was treated under the conditions of Example 320 (step 1) to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid tert-butyl ester (1.9 g). This t-Bu ester was deprotected using formic acid (19 mL) at 50° C. for 20 min. The crude product was concentrated and triturated with a mixture of ether and hexane to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (1.12 g). To a solution of 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (561 mg, 2 mmol) and triethylamine (1.1 mL, 8 mmol) in THF (9 ml), isobutyl chloroformate (0.31 mL, 2.4 mmol) was added dropwise at −78 ° C. After being stirred for 1 h, hydrazine hydrate (1 mL, 11 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and concentrated. A small amount of ice was added to quence any excess reagent and precipitate the product, which was collected by filtration to give 482 mg of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Br[C:20]1[C:21]([N+:27]([O-:29])=[O:28])=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:17]([O:16][C:14]([C:9]1[CH:10]=[N:11][N:12]([CH3:13])[C:8]=1[NH:7][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N+:27]([O-:29])=[O:28])=[O:15])[CH3:18]
Reactant: Cc1cccc(Br)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(C)c1Nc1cccc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
Cesium carbonate (35.2 g, 108 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.4 g, 0.7 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.2 g, 0.2 mmol) were added to a solution of ethyl 5-amino-1-methylpyrazole-4-carboxylate (15.3 g, 90 mmol) in dioxan (50 ml) under an inert atmosphere. A solution of 3-bromo-2-nitrotoluene (16.2 g, 75 mmol) in dioxane (10 ml) was added and the mixture was stirred for 30 min at room temperature then heated at reflux for 72 h. The suspension was filtered through Celite® filter agent, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% pet. ether) then recrystallised from EtOAc/pet. ether to yield the title compound (12.5 g, 45%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][CH:14]=[CH:15][C:8]=12)(C)C.[F:16][C:17]1[C:22]([CH:23]=[O:24])=[C:21]([F:25])[CH:20]=[CH:19][C:18]=1[NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[OH-].[K+].[Cl-].[NH4+]>O.CO>[C:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][CH:14]=[C:15]([CH:23]([OH:24])[C:22]3[C:17]([F:16])=[C:18]([NH:26][S:27]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)(=[O:29])=[O:28])[CH:19]=[CH:20][C:21]=3[F:25])[C:8]=12)#[CH:5]
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Reactant: C[Si](C)(C)C#Cc1ccnc2[nH]ccc12
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C#Cc1ccnc2[nH]cc(C(O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
Into a round bottom flask 4-trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine (7, 0.250 g, 1.17 mmol), N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (4, 0.498 g, 1.36 mmol), and 2.0 mL of methanol were added and the suspension was stirred for 10 minutes. Potassium hydroxide (0.213 g, 3.79 mmol) was added and the reaction was stirred at room temperature for 6 hours. The reaction was poured into 25 mL of water and 25 mL of saturated ammonium chloride, then extracted with 50 mL or ethyl acetate. The organic layer was isolated and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with a gradient of 5 to 60% ethyl acetate in hexanes. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (8, 0.146 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)#[CH:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:42][CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52](=[O:64])[C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=2[C:60]([F:63])([F:62])[F:61])[CH2:48][CH2:47]1)=[O:45]>CN(C=O)C.O>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:42][CH2:43][C:44]([N:46]2[CH2:47][CH2:48][N:49]([C:52](=[O:64])[C:53]3[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=3[C:60]([F:62])([F:61])[F:63])[CH2:50][CH2:51]2)=[O:45])=[O:18])=[CH:19][CH:20]=1)#[CH:11]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: C#Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 41.4 %

Procedure:
DIPEA (263.67 mg, 0.34 mL, 2.04 mmol) was added to a stirred solution of 4-Ethynyl-benzoic acid (100 mg, 0.68 mmol) in DMF (1.5 mL). HOBT (92 mg, 0.68 mmol) and EDCI (156.42 mg, 0.81 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (253 mg, 0.68 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with 5% sodium bicarbonate solution followed by brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was recrystallized from a mixture of EtOAc and ether to afford 130 mg (41.1% yield) of 4-Ethynyl-N-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide. LCMS Purity: 87.29%. 1H NMR (DMSO-d6): δ 8.7 (m, 1H), 8.0-7.8 (m, 3H), 7.6-7.4 (m, 4H), 4.4 (s, 1H), 4.2-4.1 (m, 2H), 3.8-3.4 (m, 3H), 3.2-3.0 (m, 2H).
Reaction SMILES: [CH2:1]1[NH:13][CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:14](=[O:17])[NH:15][N:16]=[C:2]1[C:3]=2[C:4]=34.[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O.CN1CC2NC3C=CC=C4C(=O)NN=C(C=2C=34)C1>>[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][N:13]1[CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:14](=[O:17])[NH:15][N:16]=[C:2]([C:3]=2[C:4]=34)[CH2:1]1
Reactant: CC(C)(C)CC=O
Reactant: O=C1NN=C2CNCc3[nH]c4cccc1c4c32
Agent: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Product: CC(C)(C)CCN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 54 was prepared from 2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one and 3,3-dimethylbutanal according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 9.89 (s, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=7.2 Hz), 7.13 (dd, 1H, J=7.2, 7.8 Hz), 3.81 (br s, 2H), 3.29 (br s, 2H), 2.57-2.58 (m, 2H), 1.43-1.46 (m, 2H), and 0.91 (s, 9H). MS (ESI) m/e [M+1]+ 311.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C@:18]([NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([CH3:22])[CH2:19][CH:20]=[O:21].[Na+].[Cl-].C(OC(=O)C)C>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C@:18]([NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([CH3:22])[CH2:19][C@H:20]([OH:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(CC=O)c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](C)(C[C@H](O)c1ccccc1)c1cc([N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.3 %

Procedure:
To a solution of the chlorotitaniumtriisopropoxide (6.57 g, 25.2 mmol) in 80 mL dry THF at 0° C. was slowly added phenyllithium (2.0M solution in dibutylether, 12.6 mL, 25.2 mmol) and the mixture was stirred at 0° C. for 30 min, followed by a slow addition of a solution of (R)-2-Methyl-propane-2-sulfinic acid [(S)-1-(2-fluoro-5-nitro-phenyl)-1-methyl-3-oxo-propyl]-amide (4.2 g, 12.6 mmol) in 30 mL dry THF. The resulting reaction mixture was let to warm up to 23° C. and stirred at 23° C. for 2 h. The reaction medium was slowly poured into a stirred mixture of a saturated NaCl aqueous solution and ethylacetate, which was stirred for 15 min until precipitation occured. The suspension was filtered over celite, the filtrate was poured in a reparatory and extracted with water. The collected organic phase was dried over Na2SO4 and removal of solvent in vaccum yielded a crude yellow oil. The crude was purified by chromatography on silica using a mixture of heptane and ethylacetate which gave the desired diastereoisomer (R)-2-Methyl-propane-2-sulfinic acid [(1S,3S)-1-(2-fluoro-5-nitro-phenyl)-3-hydroxy-1-methyl-3-phenyl-propyl]-amide (1 g, 2.43 mmol, yield: 19.3%). MS (ISP): m/z=409.3 [(M+H)+] and a second diastereoisomer (R)-2-Methyl-propane-2-sulfinic acid [(1S,3R)-1-(2-fluoro-5-nitro-phenyl)-3-hydroxy-1-methyl-3-phenyl-propyl]-amide (2.6 g, 6.32 mmol, yield: 50.2%). MS (ISP):m/z=409.0 [(M+H)−].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[H][H]>C(O)C.[Pd]>[NH2:10][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([CH3:9])=[CH:6][C:4]=1[NH2:5]
Reactant: [H][H]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(N)c(N)c1
Yield: 99.9 %

Procedure:
2.50 g (15.0 mmol) of 3,5-Dimethyl-2-nitroaniline are dissolved in 50 ml ethanol. To this solution 250 mg (0.23 mmol) of palladium (10% on carbon) are added under argon. The mixture is treated for 24 h with hydrogen at ambient pressure and ambient temperature. The mixture is filtrated over celite and washed with ethanol. The solvent is evaporated under vacuum to yield 2.04 g (97.1% of th.) of 2-Amino-3,5-dimethylphenylamine.
Reaction SMILES: CO[C:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]=1.Cl.[NH2:11][CH:12]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH2:16][CH2:15][C:14]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:13]1=2.Cl>CCOCC.C(O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:14]2[CH2:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH:12]([N:11]=[C:3]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:4]3)[C:13]=2[CH:25]=1
Reactant: NC1c2cc(Cl)ccc2CCc2sccc21
Reactant: COC1=NCCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Clc1ccc2c(c1)C(N=C1CCCCCN1)c1ccsc1CC2

Procedure:
5 ml of 98% ethanol and 10.0 g of caprolactim 0-methyl ether are added to 8.0 g of 4-amino-6-chloro-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene hydrochloride and are allowed to stand at room temperature while shaking occasionally. A few drops of ether are added to the resulting clear solution after 12 hours, whereupon the hydrochloride of the title compound crystallizes. M.Pt. decomp. from 185°, (recrystallized once from ethanol/ether).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.C(O)(=[O:16])C>C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:4]([O:12][C:5](=[O:16])[NH:6][C:7]2=[CH:8][CH:9]=1)=[O:13]
Reactant: CC(=O)O
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2ccc(Cl)c(Cl)c2c(=O)o1

Procedure:
49 g (0.226 mol) of 4,5-dichloroisatin are suspended in 200 ml of acetic acid and 200 ml of acetic anhydride, treated over a period of 50 minutes at a temperature between 80° and 90° with 37.65 g (0.376 mol) of chromium trioxide and the mixture is subsequently cooled to 5°. The precipitated material is filtered off under suction, washed with water and dried. There is obtained 5,6-dichloroisatoic acid anhydride of melting point 280°-283°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]CC(Cl)(Cl)Cl)[N:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CS(C)=O.O.C(OCC)(=O)C>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[O:35])[N:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccccc2)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(-c2ccccc2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (160 mg, 0.52 mmol) and 2,2,2-trichloroethyl (3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)carbamate (200 mg, 0.52 mmol) in dimethylsulfoxide/water (2.0 mL/1.5 mL) was added triethylamine (53 mg, 0.52 mmol), and the mixture was stirred at 85° C. for 8 hr. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) and precipitated from ethyl acetate/diisopropyl ether/hexane to give the title compound (285 mg, 99%) as a white powder.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][CH3:33]>>[CH2:32]([C:31]1[N:27]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:28][CH:30]=1)[CH3:33]
Reactant: CCC(=O)CBr
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CCc1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (about 0.211 mmol) of the compound from Example 115A and 38 mg (0.253 mmol) of 1-bromobutan-2-one were reacted according to the General Method 3. Yield: 49 mg (47% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(O)(O)(=O)=O.[NH2:44][CH2:45][C:46]#[N:47].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22](=[O:23])[NH:47][CH2:46][C:45]#[N:44])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: N#CCN
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCC#N)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), aminoacetonitrile sulfate (85 mg, 0.41 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.206 g, 0.81 mmol) and triethylamine (0.37 mL, 2.7 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(cyanomethyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 4a (150 mg, yield 94.4%) as a white solid.