Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:34]C(OC)=O)[CH2:20][C@@H:21]3[O:29]C(OC)=O)=[CH:16][CH:15]4[O:39]C(OC)=O)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C[O-].[Na+]>CO.O>[CH3:44][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:34])[CH2:20][C@@H:21]3[OH:29])=[CH:16][C@H:15]4[OH:39])[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: COC(=O)OC1C=C2C[C@@H](OC(=O)OC)C[C@H](OC(=O)OC)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
In 5 ml of methanol was dissolved 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β,7-tris(methoxycarbonyloxy)pregn-5-ene, followed by addition of 30 mg of sodium methoxide, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured in water and extracted with methylene chloride. The extracts were pooled, washed with aqueous sodium chloride solution and concentrated under reduced pressure. The concentrate was recrystallized from ethyl acetate to give 65 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-5-ene-1α,3β,7α-triol showing the following physical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>>[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])=[CH:35][CH:34]=1)(=[O:31])=[O:32]
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cl
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)cc1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 4-methylsulphonylbenzylamine hydrochloride (42 mg, 0.19 mmol). Yield: 38 mg (43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[CH:15][C:16](Br)=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:38])[C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[CH:15][C:16]([C:23]3[CH:22]=[C:21]([C:20]([O:19][CH3:18])=[O:38])[CH:26]=[CH:25][C:24]=3[C:27]#[N:28])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)cncc21
Product: COC(=O)c1ccc(C#N)c(-c2cncc3c2ccn3C(=O)OC(C)(C)C)c1

Procedure:
Using 4-bromo-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (synthesized based on US 2005/0090529 A1, p82) (1 mol. eq.) and 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.0 mol. eq.) a starting materials, the reaction was performed using General procedure L (Suzuki) to give 4-(2-cyano-5-methoxycarbonyl-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester. MS(ESI) m/z 378.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[N:14][CH:15]=1.CCO.Cl>O>[Br:9][C:10]1[CH:11]=[N:12][C:13]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:14][CH:15]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Fc1cccc(Nc2ncc(Br)cn2)c1
Temperature: 50 °C

Procedure:
In a microwave vial is added 3-fluorophenylamine (0.293 mL, 2.58 mmol), 5-bromo-2-chloropyrimidine (500 mg, 2.58 mmol), EtOH (10 mL) and concentrated HCl (0.2 mL). The reaction mixture is then heated at 50° C. for 15 min. Water (20 mL) is added and it is extracted with EtOAc. The organic layer is washed with NaHCO3, dried with Na2SO4 and concentrated. The residue is purified by column chromatography to give the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.83-6.88 (m, 1H) 7.24-7.26 (m, 1H) 7.28 (br. s., 1H) 7.34-7.40 (m, 1H) 7.74 (dt, J=11.37, 2.27 Hz, 1H) 8.56 (s, 2H); (M+H)+269.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.BrC1C=C2C(=CC=1)C(=O)N([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)C=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)c(Cl)cc12
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Product: COc1ccc(Cn2ccc3cc(Br)c(Cl)cc3c2=O)cc1

Procedure:
Starting from 6-Bromo-7-chloro-2H-isoquinolin-1-one (12), the title compound was prepared by the method described for 6-Bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (compound 13). Rt=2.12 min (Method B). Detected mass: 378.1/380.1 (M+H+).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:4]([Cl:22])=[C:5]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:6]([F:11])=[C:7]([CH2:9]Br)[CH:8]=1>C(Cl)Cl>[NH2:1][CH2:9][C:7]1[C:6]([F:11])=[C:5]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:4]([Cl:22])=[C:3]([Br:2])[CH:8]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)c(CBr)cc(Br)c2Cl)c1
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(CN)cc(Br)c2Cl)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
To an ammonia (7.0 M solution in MeOH) (60.0 ml, 2771 mmol) solution was added 3-{[3-bromo-5-(bromomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile in DCM (40 ml) dropwise at 0° C. and the reaction mixture was allowed to warm to rt overnight. The solvent was removed, the residue dissolved in EtOAc and the mixture was neutralized with saturated sodium bicarbonate. The solvent was removed and the crude material was purified via silica gel chromatography to give the title compound 3-{[3-(aminomethyl)-5-bromo-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (801 mg, 2.054 mmol, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (d, 1H), 7.77 (s, 1H), 7.25-7.60 (m, 2H), 3.72 (s, 2H), 1.98 (br. s., 2H)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOP(=O)(NC1CNCCC1C)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1C)OCC
Temperature: 70 °C
Yield: 52 %

Procedure:
To a solution of diethyl 4-methylpiperidin-3-ylphosphoramidate (1.0 equiv.) in isopropyl alcohol was added 4-chloro-3-nitropyridine (2.0 equiv.) and DIEA (1.1 equiv.). The reaction was heated to 70° C. for 18 h, then quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuo. The crude was purified via ISCO (ethyl acetate and hexanes) to yield diethyl 4-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate in 52% yield. LCMS (m/z): 373.0 (MH+), Rt=1.93 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 43 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (457 mg, 3.0 mmol, prepared generally according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) and 2-fluoro-4-nitrophenol (706 mg, 4.5 mmol), and N,N-diisopropylethylamine (580 mg, 4.5 mmol) in 1-methyl-2-prolidinone (NMP) (3 mL) was heated at 200° C. under microwave irradiation for 1 h. The mixture was diluted with ethyl acetate (150 mL), washed with sat. aq. KH2PO4 solution, and Na2CO3 (aq. 1 M), and dried over Na2SO4. The product was purified by flash column chromatography (silica gel, eluting with CH2Cl2 to 30% EtOAc/CH2Cl2) to afford the desired compound (350 mg, 43%) as a brown solid. MS(ESI+) m/z 274 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([F:24])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O.ClCCl>[F:24][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[C:20]([F:22])([F:21])[F:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(N2CCNCC2)ccc1C(F)(F)F
Yield: 77.8 %

Procedure:
4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (853 mg, 2.45 mmol) was stirred in a mixture of trifluoroacetic acid/dichloromethane (5 mL, 25% v/v) for 20 min at room temperature. The reaction mixture was combined with 25 mL of CH2Cl2 and was washed with sat'd NaHCO3 (2×10 mL) and brine. The resulting CH2Cl2 layer was dried over anhydrous Na2SO4 and was concentrated to yield crude amine. The product was further purified by silica gel chromatography (gradient eluent 0-10% MeOH in dichloromethane) to provide 4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine (473 mg, 78%). The product was used directly in step 3.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[CH2:5]([OH:9])[CH:6]([CH3:8])[CH3:7]>>[C:2]([O:9][CH2:5][CH:6]([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: CC(C)CO
Product: CC(C)COC(C)(C)C

Procedure:
In the etherification step, isobutene is reacted with alcohols, preferably with isobutanol, over an acid catalyst, preferably over an acid ion exchanger, to form ethers, preferably isobutyl tert-butyl ether. In one embodiment of the invention, the reaction is carried out in a three-stage reactor cascade in which the reaction mixture flows from the top downward through flooded fixed-bed catalysts. In the first reactor, the inlet temperature is from 0 to 60° C., preferably from 10 to 50° C.; the outlet temperature is from 25 to 85° C., preferably from 35 to 75° C., and the pressure is from 2 to 50 bar, preferably from 3 to 20 bar. At a ratio of isobutanol to isobutene of from 0.8 to 2.0, preferably from 1.0 to 1.5, the conversion is from 70 to 90%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:16][C:15]([C@@H:17]3[CH2:21][C@H:20]([OH:22])[CH2:19][N:18]3[C:23](=[O:33])[C@@H:24]([NH:28][C:29](=[O:32])[O:30][CH3:31])[CH:25]([CH3:27])[CH3:26])=[N:14][CH:13]=1)[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([C:48]3[NH:52][C:51]([C@@H:53]4[CH2:57][CH2:56][CH2:55][N:54]4[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:50][CH:49]=3)=[CH:44][CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:22][C@@H:20]1[CH2:19][N:18]([C:23](=[O:33])[C@@H:24]([NH:28][C:29]([O:30][CH3:31])=[O:32])[CH:25]([CH3:26])[CH3:27])[C@H:17]([C:15]2[NH:16][C:12]([C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[CH:3]=[C:2]([C:42]3[CH:43]=[CH:44][C:45]([C:48]5[NH:52][C:51]([C@@H:53]6[CH2:57][CH2:56][CH2:55][N:54]6[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:50][CH:49]=5)=[CH:46][CH:47]=3)[CH:11]=[CH:10]4)=[CH:13][N:14]=2)[CH2:21]1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 42.9 %

Procedure:
To a solution of methyl (S)-1-((2S,4S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (100 mg, 0.19 mmol) in DME (2 mL) was added (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (83 mg, 0.19 mmol), Pd(PPh3)4 (22 mg, 0.019 mmol), and K2CO3 (2M in H2O, 0.32 mL, 0.63 mmol). The solution was degassed with N2 for 10 min, then heated to 85° C. for 18 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (61 mg).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[CH:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:58])[CH3:57])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:63])[CH3:62])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][C:81]([OH:84])([CH3:83])[CH3:82])[N:10]([CH3:85])[C:8](=[O:9])[CH2:7][N:6]([CH3:86])[C:4]1=[O:5].[H][H]>C(O)C.[Pd]>[CH3:53][CH2:52][CH2:51][CH2:50][C@H:48]([C@@H:47]([OH:54])[CH:43]1[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:57])[CH3:58])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:62])[CH3:63])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:67])[CH3:68])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:74])[CH3:75])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][C:81]([OH:84])([CH3:82])[CH3:83])[N:10]([CH3:85])[C:8](=[O:9])[CH2:7][N:6]([CH3:86])[C:4](=[O:5])[C@H:3]([CH2:2][CH3:1])[NH:46][C:44]1=[O:45])[CH3:49]
Reactant: [H][H]
Reactant: C/C=C/C[C@@H](C)[C@@H](O)C1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)(C)O)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Agent: [Pd]
Solvent: CCO
Product: CCCC[C@@H](C)[C@@H](O)C1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)(C)O)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C

Procedure:
To a suspension of 200 mg pre-hydrogenated 10% palladium/charcoal in 4 ml ethanol is added 1.2 g of [γ-hydroxy-MeLeu]4 -Ciclosporin (compound e) in 10 ml ethanol and hydrogenation is carried out at room temperature until no more hydrogen is taken up. After removal of the catalyst by filtration the solution is evaporated, yielding the title compound as an amorphous white powder, m.p. 154-156°, [α]D20 -225° (c=0.87 in CHCl3), -169° (c=0.70 in CH3OH).
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33][CH3:34])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:35]([OH:37])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:38][N:39]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>O.CN(C)C=O>[C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33][CH3:34])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH:11]([C:35]([NH:39][OH:38])=[O:37])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Product: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)NO)cc1
Yield: 54.9 %

Procedure:
The procedure of Example 45 was followed using the product from Example 44 (230 mg, 0.444 mmol), 1-hydroxybenzotriazol (72 mg, 0.533 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (111 mg, 0.579 mmol), hydroxylamine in water 50% solution (0.217 ml, 3.55 mmol) in dimethylformamide (3 ml) to give 130 mg (55%) of the product.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[C:13]([C:17]([F:20])([F:19])[F:18])=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:21]([SH:24])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:21]([S:24][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([C:17]([F:20])([F:19])[F:18])=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:22][CH3:23]
Reactant: CCCS
Reactant: COC(=O)c1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(=O)OC
Yield: 18 %

Procedure:
1.52 g (5.0 mmol) of methyl 2-chloro-4-(3-trifluoromethylpyrazolyl)benzoate, 0.66 g (8.6 mmol) of 1-propanethiol and 0.83 g (6.0 mmol) of potassium carbonate were stirred in 5 ml of N,N-dimethylformamide at 60° C. for 24 hours. The resulting reaction mixture was poured into 50 ml of water, and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by thin layer chromatography afforded 0.31 g of methyl 2-propylthio-4-(3-trifluoromethylpyrazolyl)benzoate as a white powder (m.p. 114-116° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:14])[CH:3]=1.S(Cl)([Cl:17])=O>ClC(Cl)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1cc(N)c([N+](=O)[O-])cc1C(=O)Cl

Procedure:
Prepared analogously to example 53a from 4-amino-2-methyl-5-nitro-benzoic acid and thionyl chloride in dichloroethane.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:14]O>>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH3:14])=[O:5]
Reactant: CO
Reactant: CC(C)(CO)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)CO
Yield: 57.2 %

Procedure:
3-Hydroxy-2,2-dimethylpropanoic acid (15.00 g, 127.0 mmol) was dissolved in a solution of MeOH (200 mL) and conc. H2SO4 (13.5 g, 254 mmol) and stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with water (2×50 mL), sat. NaHCO3 (aq) (50 mL), water (50 mL), brine (1×50 mL), and dried (Na2SO4). Organic solvent was removed in vacuo to afford methyl 3-hydroxy-2,2-dimethylpropanoate (6.4 g, 57.2%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 3.71 (s, 3H), 3.56 (s, 2H), 2.05-2.04 (m, 1H), 1.19 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[C:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2/[CH:24]=[CH:23]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:42][CH:43]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 92 %

Procedure:
A solution of 2 g (3.6 mmol) of methyl E-4-[2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-enyl]benzoate (Example 17A) in 8 ml of dry acetonitrile is mixed with 2.20 g (9.71 mmol) of 4-(tert-butyl)benzyl bromide and 2.02 g (14.59 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 1.9 g (3.30 mmol, 97% purity, 92% yield) of an oil are isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11](/[CH:13]=[C:14]3/[C:15](=[O:23])[NH:16][C:17]4[C:22]/3=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[O:12][C:11](/[CH:13]=[C:14]3/[C:15](=[O:23])[NH:16][C:17]4[C:22]/3=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:10][CH:9]=2)[CH:3]=1)=[O:28]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Solvent: ClCCl
Product: O=C(CCCl)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Reaction time: 0.33 h

Procedure:
To a solution of (E)-3-((5-(3-aminophenyl)furan-2-yl)methylene)indolin-2-one (80 mg, 0.26 mmol) and TEA (0.11 mL, 0.79 mol) in DCM (5.0 mL) was added 3-chloropropanoyl chloride (0.04 mL, 0.42 mmol). The reaction was stirred for 20 min and the precipitate was collected by filtration to yield desired (E)-3-chloro-N-(3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenyl)propanamide. LCMS (ES): m/z 357 [M+1-Cl]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:22]([CH3:23])[CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1[nH]c2ccc(CCN(C)C3CCOCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a mixture of 2-methyl-5-(2-methylamino-ethyl)-1H-indole-3-carboxylic acid benzyl ester (403 mg, 1.25 mmol) and tetrahydro-4H-pyran-4-one (0.115 ML, 1.25 mmol) in dichloroethane (10 mL) was added sodium triacetoxyboro hydride (371 mg, 1.75 mmol) followed by acetic acid (0.071 mL, 1.25 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours and then partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was purified by chromatography (5% methanol in methylene chloride) to give 270 mg (53%) of the desired product as a white foam: mp 109-11 1° C.; MS(APCI+): m/z 407.2 (MH+); Anal. Calcd for C25H30N2O3.0.25H2O: C, 73.05; H, 7.48; N, 6.82. Found: C, 72.86; H, 7.59; N, 6.78.