Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.C(Cl)Cl.C([O:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:35][CH2:34][C:33]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=4[NH:31][C:30]3=[O:42])[CH2:25][CH2:24]2)[CH:20]=[C:19]([C:43]([C:45]2[CH:55]=[C:54]([CH3:56])[C:48]3[N:49]([CH3:53])[C:50](=[O:52])[O:51][C:47]=3[CH:46]=2)=[O:44])[CH:18]=1)C1C=CC=CC=1>[Pd].CO>[CH3:53][N:49]1[C:48]2[C:54]([CH3:56])=[CH:55][C:45]([C:43]([C:19]3[CH:20]=[C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:35][CH2:34][C:33]6[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=6[NH:31][C:30]5=[O:42])[CH2:25][CH2:24]4)[NH:22][C:17](=[O:16])[CH:18]=3)=[O:44])=[CH:46][C:47]=2[O:51][C:50]1=[O:52]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(OCc4ccccc4)n3)CC1)C(=O)N2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(=O)[nH]3)CC1)C(=O)N2
Reaction time: 1.5 h

Procedure:
30 mg palladium on charcoal (Pd/C 10%), 30 mL THF and 30 mL DCM were added to 0.13 g (0.20 mmol) 3-[6′-benzyloxy-4′-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 20 mL MeOH and the mixture was hydrogenated for 1.5 h under a hydrogen atmosphere. After filtration of the reaction mixture the solvent was evaporated down i. vac. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:29][CH:30]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Cc1cccc2c(C3=CCNCC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.499 g, 2.4 mmol) and 7-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.509 g, 2.4 mmol) in the presence of 2.0 equivalents of K2CO3 (0.593, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.383 g (41%) of a tan powder. mp 166-169 C. FDMS m/e=405 (M+ of free base).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[C:10]2[N:12]([Si](C(C)C)(C(C)C)C(C)C)[CH:13]=[CH:14][C:9]2=[CH:8][CH:7]=1.[CH3:26][N:27](C=O)C.ClS(N=C=O)(=O)=O.[Na+].[Cl-]>C(#N)C>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[C:10]2[NH:12][CH:13]=[C:14]([C:26]#[N:27])[C:9]2=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(NCCN(C)C)nc21
Agent: O=C=NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCNc1ccc2c(C#N)c[nH]c2n1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
In a 25 mL round-bottomed flask, N1,N1-dimethyl-N2-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)ethane-1,2-diamine (405 mg, 1.12 mmol) was combined with DMF (14.9 ml) to give a colorless solution. The reaction mixture was cooled to −20° C. and stirred for 5 min. Chlorosulfonyl isocyanate (477 mg, 293 μl, 3.37 mmol, Eq: 3) in acetonitrile (14.9 ml) was added dropwise and the resultant cooled reaction was stirred at −20° C. and stirred for 3 hrs The reaction mixture was poured into 25 mL sat NaCl and extracted with EtOAc (3×20 ml). After evaporation, crude material was purified by flash chromatography (silica gel, 12 g, 5% to 10% MeOH in DCM) to obtain 6-(2-(dimethylamino)ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (211 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][F:18])[N:3]=1.NC1N=C(N)C(C2C=C([Cl:33])C=C(Cl)C=2Cl)=C(CO)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:33])[CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][F:18])[N:3]=1
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(CO)n1
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CF)n1
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(CF)n1

Procedure:
This compound was prepared in an analogous manner to the compound of Example 18 from 2,4-diamino-5-(2,3,5-trichlorophenyl)-6-hydroxymethylpyrimidine, mp. 215°-217° C.
Reaction SMILES: [CH2:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:9][CH:10]=[CH2:11])[C:5]([O:7][CH3:8])=[O:6])C=C>ClCCl>[C:12]1([C:4]2([C:5]([O:7][CH3:8])=[O:6])[CH2:1][CH:11]=[CH:10][CH2:9]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCC(CC=C)(C(=O)OC)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C1(c2ccccc2)CC=CC1
Yield: 90.4 %

Procedure:
To a solution of methyl 2-allyl-2-phenylpent-4-enoate (378 mg) in dichloromethane (41 mL) was added benzylidene-bis(tricyclhexylphosphine)dichlororuthenium (68 mg) and the resulting suspension was heated under reflux for 1 h. The solvent was removed in vacuo, and the crude product was purified by preparative TLC eluting with 10% ethyl acetate/90% hexanes to give the title compound as an oil (300 mg). 1H NMR (400 MHz, CDCl3) δ 2.74 (2H, d, J=14.8 Hz), 3.40 (2H, d, J=14.8 Hz), 3.63 (3H, s), 5.76 (2H, s), 7.22-7.31 (5H, m). 13C NMR (100 MHz, CDCl3) δ 42.8, 52.5, 58.4, 126.6, 126.8, 128.7, 129.2, 143.7, and 176.6.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.C[C:12]1[C:25]([CH2:26][CH2:27][CH2:28][OH:29])=[C:24]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH:23]=[CH:22][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C>C(Cl)Cl.O>[CH:28]([CH:27]([CH3:1])[CH2:26][C:25]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])=[O:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C(=O)c2ccccc2)ccc(OC(=O)C(C)(C)C)c1CCCO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C=O)Cc1cc(C(=O)c2ccccc2)ccc1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.8 ml of oxalyl chloride in 43 ml of methylene chloride were added dropwise a solution of 3.0 ml of DMSO in 9 ml of methylene chloride at -60° C., and then a solution of 6.14 g of 3-(2-methylhydroxypropyl-4-pivaloyloxybenzophenone in 17 ml of methylene chloride. The mixture was stirred at about -50°-60° C. for 15 min, then treated with 12.1 ml of triethylamine. The reaction mixture was stirred at -50° C. for 5 min, warmed to 25° C., and then treated with 85 ml of water. The organic layer was washed with dilute hydrochloric acid and then with brine, dried (MgSO4) and concentrated to give 5.0 g of product as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH:7]=[C:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl.[CH3:18][CH2:19]O>>[CH2:18]([O:10][C:9](=[O:11])[C:8](=[CH:7][C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:12][CH3:13])[CH3:19]
Reactant: CCC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)CC

Procedure:
2-(3-Nitro-benzylidene)-butyric acid (500 mg, 2.27 mmol) was esterified by dissolving in EtOH (12.5 ml), adding conc HCl (0.25 ml) and heating to reflux for 8 h. The solvents were evaporated in vacuo to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.C[O:21][C:22]1[N:23]=[N:24][C:25]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:26][C:27]=1[C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>>[C:1]([C:36]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][C:28]=1[C:27]1[C:22](=[O:21])[NH:23][N:24]=[C:25]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1c(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]c2ccccc12
Temperature: 0 °C
Yield: 48.1 %

Procedure:
4 mg acetyl chloride are added at 0° C. to a suspension of 80 mg aluminum chloride 1,2-Dichloroethane, followed by 208 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole Trifluoroacetate. The reaction mixture is stirred for 4 h at room temperature and for 3h at 50° C. It is worked up pouring into an ice/water mixture and filtration. The layers are separated, the organic is layer washed with water, dried over MgSO4 and the solvent removed. Reverse phase HPLC chromatography yielded 8.1 mg 4-(3-Acetyl-1H-indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:13].[H-].[Na+].C([Li])(C)(C)C.CCCCC.Cl.[C:27](=O)(O)[O-:28].[Na+]>CN(C)C=O.O1CCCC1>[CH2:11]([C:9]1[CH:10]=[C:2]([CH:27]=[O:28])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[C:5]2[CH3:13])[CH3:12]
Reactant: CCc1cc(Br)cc2c(C)n[nH]c12
Reactant: O=C([O-])O
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCc1cc(C=O)cc2c(C)n[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
5-Bromo-7-ethyl-3-methylindazole (2.85 g, 11.9 mmol) and sodium hydride (0.31 g, 1.1 equiv.) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (15 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to −78° C. and a solution of tert-butyllithium in pentane (1.4M, 18.7 mL, 2.0 equiv) was added over several minutes. After 1 h at −78° C., dimethylformamide (2.8 mL) was slowly added and the mixture allowed to warm to room temperature overnight. The solution was cooled to 0° C. and carefully treated with 1N hydrochloric acid (30 mL). After a few minutes, solid sodium bicarbonate was added until a pH of 9-10 was attained. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography gave 1.5 g (67%) of pure material. LC/MS: tR=1.15 min, 189.12 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:31][CH2:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NCC1CCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC3CCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclobutylmethanamine as an off-white solid (67%). MS 414 (MH+).
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[N:25]1([C:29](=S)[NH:30][NH2:31])[CH2:28][CH2:27][CH2:26]1>CC(O)=O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[C:2]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=3)[N:18]=2)=[C:29]2[NH:25][CH2:26][CH2:27][CH2:28][N:30]2[N:31]=1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: NNC(=S)N1CCC1
Solvent: CC(=O)O
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nn4c3NCCC4)nn12
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 26.3 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.61 g, 1.54 mmol; Preparation #A.2) and azetidine-1-carbothiohydrazide (0.29 g, 2.20 mmol) in HOAc (5 mL) was stirred at about 55° C. for about 1-2 h. The reaction mixture was cooled to ambient temperature overnight and partitioned between DCM and water. The aqueous layer was basified with a saturated aqueous solution of Na2CO3 and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by chromatography on silica gel using DCM/MeOH (gradient, 100:0 to 90:10), stirred overnight with Et2O/DCM (100:10), and collected by vacuum filtration to give the title compound (0.16 g, 26%): LC/MS (Table 1, Method a) Rt=2.98 min; MS m/z: 396.2 (M+H)+; 1H NMR (CDCl3) δ 7.76 (d, J=9.89 Hz, 1H), 7.56-7.51 (m, 1H), 7.11-6.99 (m, 1H), 6.98-6.87 (m, 1H), 6.73 (dd, J=9.89, 1.83 Hz, 1H), 6.44 (s, 1H, broad), 4.2 (t, J=6.08 Hz, 2H), 3.61-3.58 (m, 2H), 3.56-3.52 (m, 1H), 2.36-2.24 (m, 2H), 1.58 (d, J=6.99 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[H][H]>C(O)(=O)C.OS(O)(=O)=O>[CH3:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: [H][H]
Reactant: COC(=O)C1(C)Cc2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)C1(C)Cc2ccccc2C1

Procedure:
A solution of the methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.04 g, 9.99 mmol) in glacial acetic acid (22 mL) and concentrated H2SO4 (2 mL) was hydrogenated on a Parr apparatus under 50 psi of hydrogen using 10% palladium on carbon (50% H2O, 0.200 g) as the catalyst. After 4 hours the reaction was filtered to remove the catalyst and washed 2× methanol, then concentrated to remove most of the acetic acid. The residue was neutralized using saturated Na2CO3 and the organics extracted twice with 25 mL ethyl acetate, then the combined organics washed with brine, dried (Na2SO4), filtered and concentrated to 2.0 g of methyl 2-methyl-2,3-dihydro-1H-indene-2-carboxylate.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][N:8]=2)(=O)[CH3:2].[CH3:22][NH:23][NH2:24]>C(O)(=O)C>[CH3:22][N:23]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5](=[O:21])[C:4]=2[C:1]([CH3:2])=[N:24]1
Reactant: CNN
Reactant: CC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CC(=O)O
Product: Cc1nn(C)c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 25 °C
Yield: 60.1 %

Procedure:
Compound 102 obtained in Example 2, 4.0 g (14.3 millimoles), was suspended in 2.5 ml of glacial acetic acid, and 1.8 ml (34.2 millimoles) of methylhydrazine was added to the suspension. The mixture was heated under reflux for 10 hours. The reaction solution was cooled to room temperature, and the precipitate was collected by filtration and recrystallized from DMF-water to give 2.5 g (yield: 60.1%) of Compound 4.
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](O)(=[O:71])[C:62]1[CH:70]=[CH:69][C:65]([C:66]([NH2:68])=[O:67])=[CH:64][CH:63]=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:61](=[O:71])[C:62]1[CH:70]=[CH:69][C:65]([C:66]([NH2:68])=[O:67])=[CH:64][CH:63]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 59.5 %

Procedure:
DIPEA (14.1 mg, 0.109 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt. (18 mg, 0.04 mmol) in DMF (1 mL). HOBT (6 mg, 0.04 mmol) and EDCI.HCl (8 mg, 0.04 mmol) were then added at room temperature. After 2 minutes, terephthalamic acid (6 mg, 0.04 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 3% methanol in chloroform as eluent) to afford 24 mg (59.5% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-terephthalamide. LCMS Purity: 97.1%, 1H NMR (DMSO-d6) δ 8.0-7.9 (s, 3H). 7.8-7.7 (d, 1H), 7.6 (m, 2H), 7.4-7.3 (d, 2H), 6.3-6.1 (bs, 1H), 5.8-5.6 (bs, 1H), 4.4-4.2 (m, 2H), 4.0-3.6 (m, 4H), 3.6-3.2 (m, 5H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:16])[C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)=[O:5])C.[Li+].[OH-]>CO.O>[CH3:16][N:9]1[C:10]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1-n1cccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1-n1cccc1

Procedure:
To a solution of 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid ethyl ester (Maybridge plc, Cornwall, UK; 20 g, 91.2 mmol) in methanol (100 mL) and water (100 mL) was added LiOH (2.4 g, 100.3 mmol). The reaction mixture was stirred at reflux for 4 hours and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl (9 mL), and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:25]3[N:8]([N:9]([CH3:26])[CH2:10][O:11][C:12]=3[C:13]=1[N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH2:15]1)[CH:7]=[C:6]([C:27]([OH:29])=[O:28])[C:5]2=[O:30].F[C:32](F)(F)[C:33](OC(=O)C(F)(F)F)=[O:34]>>[C:33]([N:19]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[C@@H:16]1[CH2:17][CH2:18][N:14]([C:13]2[C:12]3=[C:25]4[C:4]([C:5](=[O:30])[C:6]([C:27]([OH:29])=[O:28])=[CH:7][N:8]4[N:9]([CH3:26])[CH2:10][O:11]3)=[CH:3][C:2]=2[F:1])[CH2:15]1)(=[O:34])[CH3:32]
Reactant: CN1COc2c(N3CC[C@@H](Nc4nccs4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)N(c1nccs1)[C@@H]1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OCN4C)C1
Temperature: 25 °C

Procedure:
A solution of product 36b (200 mg, 0.46 mmol, 1.0 eq.) in trifluoroacetic anhydride (5 mL) is heated to 90° C. for 6 hours. The reaction medium is cooled down to room temperature, the mixture is filtered and the filtrate is concentrated under reduced pressure. The obtained residue is re-crystallized from methanol and then purified by preparative HPLC (acetonitrile/H2O gradient). The expected product is obtained as a beige solid (25 mg, 88%).
Reaction SMILES: [F:1][C:2]([F:19])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(CC)CC)C.[CH:27]([S:35](Cl)(=[O:37])=[O:36])=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:29]1([CH:28]=[CH:27][S:35]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:2]([F:1])([F:19])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)C(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C=Cc1ccccc1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (1.39 g, 0.005 mol) was dissolved in DCM (250 ml) and triethylamine (2.1 ml, 0.015 mol) was added. This was cooled to 0° C. and styrene sulphonyl chloride (CAS Number 52147-97-4, 1.11 g, 0.0055 mol) was added. Allowed to reach ambient temperature and stirred overnight. Washed with H2O and separated off the organic phase. Dried over MgSO4, filtered and evaporated to dryness to an oil which was purified by flash column chromatography (Merck 9385 silica), eluting with 80% iso-hexane/ethyl acetate to yield 1-[(-2-phenylvinyl)sulphonyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a yellow solid. Yield 650 mg (25%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([O:21][CH2:22][CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[F:20]>[Pd]>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([O:21][CH2:22][CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:20]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1F)C(=O)OC
Agent: [Pd]
Product: CCO[C@@H](Cc1ccc(O)cc1F)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 d], (2S)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to give (2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester as colorless liquid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].C1COCC1.[OH-].[Na+]>CO>[OH:27][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:16]1([CH3:28])[CH3:29]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 6.6 %

Procedure:
3β-Hydroxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (120 mg) is saponified in a mixture of 15 ml of methanol, 15 ml of THF and 0.7 ml of 1M sodium hydroxide at 50° C. After aqueous work-up and crystallisation from methanol, the title compound (7.6 mg) is isolated. Melting point: 210-213° C.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=O.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.O>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[C:3]([C:2](=[O:1])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CC(=O)CCc1ccccc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1ccccc1

Procedure:
A mixture of methyl 3-oxo-5-phenylpentanoate (10 g, 48.5 mmol), 2,6-dichlorobenzaldehyde (8.486 g, 48.5 mmol), acetic acid (0.56 ml, 9.7 mmol), and piperidine (0.24 ml, 2.42 mmol) in benzene (100 ml) was refluxed with azeotropic removal of water for 3 h. After cooling down the mixture, the whole was washed with water, NaHCO3 aqueous solution, and brine. The mixture was dried over Na2SO4 and evaporation of the solvent afforded a crude viscous oil, which was used for subsequent reaction without purification. 1H NMR data indicated that this was 1:1 mixture of E and Z isomers. 1H NMR (CDCl3) δ 7.56 and 7.60 (each s, total 1H), 7.20 (m, 8H), 3.59 and 3.83 (each s, total 3H), 3.14-2.83 (m, 4H),.