Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.[OH-:3].[Na+].[C:5]1([C:11]([N:24]=[C:25]=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO.O.C1COCC1>[CH3:25][N:24]1[CH2:11][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:9][OH:3]
Reactant: O=C=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: NN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN1CCCC[C@@H]1CO
Reaction time: 1 h
Yield: 44.9 %

Procedure:
Following the known procedure of patent EP 0 429 984 A2 (reference example 8). The resolution was identical to the above given procedure except that 4 rounds of crystallization were performed instead of the two as sited above. To a mixture of (±)-1-methyl-2-piperidinemethanol (77 g, 596 mmol) in EtOH (615 mL) was added dibenzoyl-D-tartaric acid (205 g, 573 mmol). The resulting mixture was slowly heated until a solution was obtained at which time the solution was slowly cooled with gentle stirring. After 12 h the crystals were isolated and dried to afford 131.6 g. This process was repeated: (2) EtOH (533 mL) provided 92.5 g. (3) EtOH (225 mL) provided 68 g (4) EtOH (200 mL) provided 49 g. The resulting salt was treated with 3M HCl (200 mL) which was heated to induce it to dissolve. The still warm solution was poured into a separatory funnel and extracted with ethyl acetate. The remaining aqueous layer was adjusted to pH 10 with K2CO3. The solution was extracted with CH2Cl2, dried (MgSO4) and concentrated to give 12 g of the alcohol. This alcohol (12 g, 92.8 mmol) was suspended in CH2Cl2 (200 mL) and SOCl2 added. After stirring for 12 h, the solvent was removed to provide a crude HCl salt. This salt was dissolved in EtOH (100 mL) and treated with NH2NH2 (89 mL, 1.86 mol) and heated to reflux for 12 h. NaOH (74 g) in H2O (30 mL) was added and stirred for 1 h. Half the solvent was removed and the residue extracted with ether to give a crude oil. After distillation under reduced pressure (50-60° C.) the pure hydrazine product (4.87 g) was obtained. This hydrazine (1.6 g, 11.2 mmol) was dissolved in THF (10 mL) and triphenylmethylisocyanate (3.19 g, 11.2 mmol) was added slowly. The solution was then stirred overnight and filtered to provide 650 mg of the desired product in good purity. 1H NMR (DMSO-d6): δ 1.10 (m, 2H), 1.30-1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71 (d, 1H), 3.25 (q, 1H), 3.55 (q, 1H), 4.80 (s, 2H), 7.12-7.32 (m, 15H), 8.02 (s, 1H). ESI-MS m/z 429.2 (100, M+H).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13](OC)=[O:14])=[N:11][C:10]([Cl:17])=[C:9]([Cl:18])[N:8]=1.[BH4-].[K+].[Cl-].[Li+]>O>[NH2:6][C:7]1[C:12]([CH2:13][OH:14])=[N:11][C:10]([Cl:17])=[C:9]([Cl:18])[N:8]=1
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Agent: [BH4-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Cl)c(Cl)nc1CO
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To 70 ml of dry tetrahydrofuran there was added 2-amino-5,6-dichloro-3-(methoxycarbonyl)pyrazine (8.8 g; 0.04 M), potassium borohydride (2.7 g; 0.05 M), and lithium chloride (2.1 g; 0.05 M), and the mixture was stirred at room temperature overnight (17 hours). The reaction mixture was then diluted with about 200 ml of water and chilled, after which the product crystallized, was filtered and dried (5.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C(NC(C)C)(C)C.[Li].O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1>C1COCC1>[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][CH:6]2[C:5](=[O:8])[C:4]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])=[C:3]([O:2][CH3:1])[CH2:7]2)=[CH:49][CH:48]=1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(Cc2ccc(F)cc2)C1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 81.1 %

Procedure:
To a solution of 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (200 mg, 0.86 mmol) in THF (3 ml) under N2 at −78° C. is added, dropwise, a 1.8 M solution of lithium diisopropylamine in tetrahydrofuran/heptane/ethylbenzene (0.53 ml, 0.95 mmol). The resulting solution is allowed to stir at −78° C. for 40 minutes. A solution of 4-fluorobenzyl bromide (0.16 ml, 1.3 mmol) in THF (1 ml) is then added in one portion, the reaction mixture is stirred at −78° C. for 30 minutes before being allowed to warm to room temperature over a period of 60 minutes. The reaction is quenched by the addition of saturated aqueous ammonium chloride (5 ml) and extracted with ethyl acetate (2×10 ml). The combined organics are purified by flash chromatography to give 5-(4-fluoro-benzyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (236 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[C:7](=[CH:19][NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1F)=[O:9])[CH3:4]>O1CCOCC1>[CH2:3]([O:5][C:6]([C:7]1[C:8](=[O:9])[C:10]2[C:11](=[CH:12][C:13]([F:17])=[C:14]([F:16])[CH:15]=2)[N:20]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:19]=1)=[O:25])[CH3:4]
Reactant: CCOC(=O)C(=CNC(C)(C)C)C(=O)c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C(C)(C)C)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
There was added 1.1 g (27 mmoles) of 60% sodium hydride portionwise, at a temperature between 18° C. to 22° C., to a suspension of 7.22 g (21.9 mmoles) of 3-(2,4,5-trifluorophenyl)-3-oxo-2-(((1,1-dimethylethyl)amino)methylene)propanoic acid ethyl ester in 73 mL of anhydrous dioxane. An exothermic reaction occurred. After stirring at room temperature during 1 hour, the resulting mixture was evaporated to dryness, and taken up with CH2Cl2 (150 mL) and H2O (200 mL). After decantation the organic layer was dried over MgSO4. Evaporation of dichloromethane gave 6.41 g of an amorphous solid which was washed twice with water to yield 6.08 g of titled compound.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:31])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)=[C:9]2[CH2:32][N:33]([S:37]([C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=3)(=[O:39])=[O:38])[C:34]([CH3:36])([CH3:35])[C:8]2=[N:7]1)=O)C.O.NN>CO.ClCCl>[NH2:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([NH:11][C:10]1[C:9]2[CH2:32][N:33]([S:37]([C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=3)(=[O:39])=[O:38])[C:34]([CH3:36])([CH3:35])[C:8]=2[NH:7][N:6]=1)=[O:31]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2[nH]nc(NC(=O)c3ccccc3CN)c2CN1S(=O)(=O)c1cc(F)cc(F)c1

Procedure:
To a suspension of 5-(3,5-difluoro-benzenesulfonyl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.23 g, 0.34 mmol) in methanol (15 mL) and dichloromethane (1.5 mL) was added hydrazine hydrate (50 microL, 1.02 mmol). After stirring at reflux for 1 hour the volatiles were removed under reduced pressure and the residue purified by flash chromatography on silica gel eluting with dichloromethane/methanol/7N NH3 in methanol 95:4:1 affording the title compound as colorless oil (93 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[OH-].[Na+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:7]([C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][O:1][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: N#Cc1cccc(CCO)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCCc1cccc(C#N)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 3-(2-hydroxy-ethyl)-benzonitrile (1 g; 6.79 mmol) in toluene (20 mL), was added tetrabutylammonium hydrogen sulfate (230.70 mg; 0.68 mmol; 0.10 eq.) and NaOH (20 mL; 5 M; 10 mmol) followed by the addition of tert-butyl bromoacetate (2 mL; 13.59 mmol). Reaction mixture was stirred at RT under vigorous stirring for 9 h. After this time, the aqueous phase was removed and the organic phase was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow powder (1.42 g; 80%). 1H NMR (DMSO-d6, 300 MHz) δ 7.74-7.73 (m, 1H), 7.68-7.65 (m, 1H), 7.63-7.59 (m, 1H), 7.51-7.46 (m, 1H), 3.97 (s, 2H), 3.69 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H), 1.40 (s, 9H). LC/MS (Method B): 262.1 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[F:5][C:6]1[C:7]([CH2:13][CH2:14][CH3:15])=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:3][C:2]#[CH:1])[C:7]=1[CH2:13][CH2:14][CH3:15]
Reactant: C#CCBr
Reactant: CCCc1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cccc(F)c1CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of 1.4 g (11.7 mmol) of propargyl bromide in 1 ml of dimethylformamide was added dropwise to a suspension of 1.3 g (8.4 mmol) of 3-fluoro-2-propyl-phenol and 1.7 g of potassium carbonate in 4 ml of dimethylformamide and the mixture was subsequently stirred at room temperature for one hour. The mixture was poured on to 30 ml of ice-water and extracted three times with 50 ml of dichloromethane each time. After drying concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:1). There were obtained 1.45 g (90%) of 1-fluoro-2-propyl-3-prop-2-ynyloxy-benzene as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13](=NN)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I:24]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]([I:24])=[CH2:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(=NN)C1(C)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(I)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 3-(1-hydrazono-ethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.076 g, 0.33 mmol) and triethylamine (0.169 g, 1.67 mmol) in THF (3 mL) was added dropwise a solution of iodine (0.127 g, 0.50 mmol) in THF (1 mL). The reaction mixture was stirred for 1 h at ambient temperature then concentrated in vacuo. The residue was dissolved in DCM (10 mL) and washed with aqueous Na2S2O3 (5%, 2 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 20% EtOAc in petroleum ether) to give 3-(1-iodo-vinyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.060 g, 55%), which was unstable and used without further purification. TLC: Rf=0.30 (eluting with 10% EtOAc in petroleum ether).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccccc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2cc(-c3ccccc3)no2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A mixture of methyl 4-(3-phenyl-5-isoxazolyl)benzoate (1.70 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (30 ml) and methanol (30 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (10 ml) was added. The crystals were collected by filtration and recrystallized from N,N-dimethylformamide-water to give 4-(3-phenyl-5-isoxazolyl)benzoic acid (1.56 g, yield 97%) as colorless crystals. melting point: >300° C.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH2:8]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH3:9].[OH-].[Na+].N>>[CH2:8]([O:10][CH2:11][CH2:12][N:13]([CH3:5])[C:14](=[O:16])[CH3:15])[CH3:9]
Reactant: CCOCCNC(C)=O
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: CCOCCN(C)C(C)=O
Yield: 89.9 %

Procedure:
37.8 g (0.3 mole) of dimethyl sulfate and 26.2 g (0.2 mole) of N-α-ethoxyethyl-acetamide are simultaneously added dropwise to 100 ml of 50% strength sodium hydroxide solution at 10°-15° C., while stirring intensively. The mixture is subsequently stirred for 3 hours, residual dimethyl sulfate is decomposed by adding concentrated ammonia, the phases are separated in a separating funnel, the aqueous layer is extracted several times with toluene and, after stripping off the solvent, the residue is distilled in vacuo. 26.1 g (90% of theory) of N-α-ethoxyethyl-N-methylacetamide of boiling point24 90°-94° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[CH:10]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>FC(F)(F)C(O)=O>[F:15][C:14]1[C:9]([CH:8]2[C:21]3[C:4](=[C:3]([O:2][CH3:1])[C:24]([O:25][CH3:26])=[CH:23][CH:22]=3)[CH2:5][NH:6][CH2:7]2)=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=1
Reactant: COc1cc(F)c(C(O)CNCc2cccc(OC)c2OC)cc1OC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C2CNCc3c2ccc(OC)c3OC)cc1OC
Yield: 98.9 %

Procedure:
α-[[(2,3-dimethoxybenzyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (1.0 g) was dissolved in 7 ml of trifluoroacetic acid, and after adding thereto under ice cooling, conc. sulfuric acid (0.25 ml), the mixture was stirred for 40 minutes. 0.72 g of sodium acetate was added to the reaction mixture, and the mixture was concentrated. To the residue was added chloroform and water, and the mixture was basified by addition of conc. aqueous ammonia under ice cooling. After the separating procedure, the chloroform layer was collected, washed with a saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, 0.94 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline was obtained as a syrupy matter.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39](O)=[O:40])=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:81][C@@H:82]([CH2:93][CH2:94][C:95]([O:97][CH2:98][C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)=[O:96])[C:83]([O:85][CH2:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:84].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:86]([O:85][C:83](=[O:84])[C@@H:82]([NH:81][C:39](=[O:40])[CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)[CH2:93][CH2:94][C:95]([O:97][CH2:98][C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)=[O:96])[C:87]1[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=1
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)OCC(=O)N[C@@H](CCC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-acetic acid (Example 69, 133 mg, 197 μmol), HATU (75.0 mg, 197 μmol) and Hunig's base (51.0 mg, 68.9 μL, 394 μmol) were combined with dry tetrahydrofuran (1 mL) to give an off-white suspension at room temperature. The mixture was stirred for 30 min and a solution of (S)-dibenzyl 2-aminopentanedioate hydrochloride (108 mg, 296 μmol) and Hunig's base (2 eq.) in dry tetrahydrofuran (1 mL) was added. After 1 h, the reaction mix was directly purified with reverse phase high-performance liquid chromatography to isolate the desired fraction, which was neutralized with saturated aqueous sodium carbonate solution, extracted with methylene chloride. The methylene chloride layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-2-[2-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-acetylamino]-pentanedioic acid dibenzyl ester (63 mg, 33% yield). LCMS (ES+) m/z calcd. for C52H51Cl2F2N4O9 [(M+H)+]: 983. found: 983.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[CH3:8])=[CH:4][F:5].[FH:15]>>[F:1][C:2]([F:13])([F:14])[CH:3]([C:6]([F:11])([F:12])[C:7]([F:10])([F:9])[CH3:8])[CH:4]([F:15])[F:5]
Reactant: CC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Reactant: F
Product: CC(F)(F)C(F)(F)C(C(F)F)C(F)(F)F

Procedure:
CF3 may then be added to the 3,3,4,4-tetrafluoro-1-pentene to form 2-trifluoromethyl-1,3,3,4,4-pentafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoro-1-pentene which may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,1,3,3,4,4-heptafluoropentane. The 2-trifluoromethyl-1,1,1,3,3,4,4-heptafluoropentane may then be dehydrohalogenated to form 4-trifluoromethyl-2,3,3,5,5,5-hexafluoro-1-pentene.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][N:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]4=[N:21][NH:22][C:23](=[O:24])[C:13]4=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=1[CH3:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.C(=O)(O)[O-].[Na+]>[Cu]I.CN(C)C=O>[CH3:35][C:29]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:28]=1[N:22]1[C:23](=[O:24])[C:13]2=[N:12][N:11]([CH2:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:26][CH:25]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]2=[N:21]1
Reactant: Cc1cccc(I)c1C
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc1-2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1cccc(-n2nc3c4ccccc4n(Cc4ccc(-n5cccn5)cc4)nc-3c2=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-[4-(1H-Pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (75 mg, 0.22 mmol) was dissolved in degassed. NA-dimethylformamide and treated with 1-iodo-2,3-dimethylbenzene (0.15 g, 0.66 mmol, 3 equiv), tribasic potassium phosphate (0.28 g, 1.31 mmol, 6 equiv), copper(I)iodide (42 mg, 0.22 mmol, 1 equiv) and (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (93 mg, 0.66 mmol, 3 equiv). The mixture was placed into an oil bath preheated at 110° C. for 30 minutes, cooled to ambient temperature, poured into sodium bicarbonate (25 mL, saturated aqueous) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (60:40 to 0:100; hexanes:ethyl acetate), providing the titled compound. 1H-NMR (400 MHz, CDCl3) δ 8.33-8.30 (1H, m), 7.90 (1H, d, J=2.6 Hz), 7.73-7.69 (3H, m), 7.58-7.52 (3H, m), 7.43 (2H, d, J=8.7 Hz), 7.31-7.27 (1H, m), 7.24-7.22 (2H, m), 6.47 (1H, dd, J=2.5, 1.8 Hz), 5.88 (2H, s), 2.37 (3H, s), 2.21 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 447.1931 [(M+H)+; calculated for C27H22N6O: 447.1928].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: Clc1cc(Cl)c(Cl)nn1
Solvent: CCO
Product: Clc1cc(N2CCNCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
18 g 3,4,6-trichloro-pyridazine and 34 g piperazine are suspended in 100 ml of ethanol and stirred for 30 minutes at ambient temperature. The precipitated solid is suction filtered. 500 ml of water are added to the mother liquor and the precipitated product is suction filtered. 14 g of product are obtained as a solid. M.p=111-115° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O.[OH-].[Na+]>N1C=CC=CC=1>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:4][CH:5]=1
Reactant: CN(C)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc(CNS(C)(=O)=O)c2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
4-(Aminomethyl)-1-[[2-(dimethylamino)ethyl]amino]-thioxanthen-9-one (2 g, 6 mmol) in 30 mL of dry pyridine under nitrogen was stirred at room temperature until the solution was complete. The solution was chilled in an ice-bath and 0.52 mL(6.7 mmol) of methanesulfonyl chloride in chilled pyridine was added dropwise and the mixture was stirred for 1 h at room temperature. The reaction mixture was poured into 500 mL of water containing 0.51 g of sodium hydroxide, extracted into chloroform, the organic layer was washed with water (2x) and brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue (2.5 g) was stirred in either, filtered, and dried to afford 2 g of N-[[1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]methane-sulfonamide, m.p. 126°-127° C. The free base was dissolved in MeOH and treated with methane sulfonic acid (0.48 g) to afford 2.0 g (67%) of the product as the methanesulfonate salt, m.p. 168° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)CCN(C)C
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)Nc2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a cooled (−78° C.) solution of 6-chloro-1,3-dihydro-indol-2-one (4.0 g, 24 mmol) and TMEDA (11.2 mL, 79 mmol) in THF (100 mL) was slowly added BuLi (2.2 M solution in cyclohexane, 22 mL, 48 mmol). The solution was stirred for 30 minutes at the same temperature and then iodomethane (2.2 mL, 36 mmol) was slowly added. The reaction was stirred at −20° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Chromatography (SiO2, EtOAc/Petrol 2:8) gave the title compound (2.7 g) as a pale pink solid. MS: [M+H]+=182.