Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:16]=C[C:11]3[N:12]=[CH:13]S[C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.IC1C=C[C:21]2[N:22](C=CN=2)C=1.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:13]=[CH:21][N:22]=3)[CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccc2ncsc2c1
Reactant: Ic1ccc2nccn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2nccn2c1
Yield: 55 %

Procedure:
6-(2-Chloropyridin-3-yl)imidazo[1,2-a]pyridine was synthesized in the similar to 6-(2-chloropyridin-3-yl)benzo[d]thiazole from 6-iodo-imidazo[1,2-a]pyridine (1.0 g, 4.1 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.2 g, 5.0 mmol), Pd(PPh3)4 (250 mg, 0.22 mmol) and 2M aq.Na2CO3 (7 mL, 12 mmol) in 1,4-dioxane (50 mL). Workup of the reaction mixture was carried out by sequential steps of concentrating the reaction mixture, extraction with CH2Cl2, drying over MgSO4/Celite®, filtration and concentration. The crude residue was stirred in 50% EtOAc/hexanes (40 mL). The resulting white precipitate was filtered and dried to provide 6-(2-chloropyridin-3-yl)imidazo[1,2-a]pyridine (0.52 g, 55%). 1H NMR (DMSO-d6): δ 8.73 (dd, 1H, J=0.8 and 1.8 Hz), 8.47 (dd, 1H, J=2.0 and 4.7 Hz), 8.00 (dd, 1H, J=2.0 and 7.6 Hz), 7.98 (s, 1H), 7.64 (d, 1H, J=8.8 Hz), 7.63 (s, 1H), 7.56 (dd, 1H, J=4.7 and 7.6 Hz), 7.33 (dd, 1H, J=1.8 and 8.8 Hz), Hz).LCMS: rt 3.16 min (A), purity 99%, MS (m/e) 230 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:25][C:26]([C:28]2[S:29][C:30]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:31][C:32]=2C)=[O:27])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][Si](C(C)C)(C(C)C)C(C)C)[CH2:10]1.[Li][C:42](C)(C)[CH3:43].CN(C=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1.CCOC(C)=O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:30]2[S:29][C:28]3[C:26](=[O:27])[N:25]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:42]=[CH:43][C:32]=3[CH:31]=2)=[CH:35][CH:36]=1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2C)ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Reactant: [Li]C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@@H](O)C1
Temperature: -78 °C
Yield: 33.2 %

Procedure:
Dissolve 5-(4-chloro-phenyl)-3-methyl-thiophene-2-carboxylic acid [3-methoxy-4-((R)-3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenyl]-amide (0.573 g, 0.958 mmol) in THF (10 mL). Cool the mixture to −78° C. under argon. Add t-BuLi (1.2 mL, 2.11 mmol) dropwise and stir at −78° C. for 20 min. Add DMF (1.5 mL) and stir at −78° C. for 10 min, then warm gradually to 0° C. Quench the mixture with saturated NH4Cl (10 mL) then dilute with EtOAc (100 mL) and wash with water (2×30 mL). Dry the solution with Na2SO4, filter, and concentrate. Suspend the resulting crude material in toluene (40 mL) and treat with p-toluenesulfonic acid-H2O (0.45 g, 2.37 mmol). Reflux the mixture using a Dean-Stark trap. Dilute the mixture with EtOAc (150 mL) and wash with saturated NaHCO3 (2×50 mL). Dry the solution with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 100% EtOAc to give 0.144 g (33%) of 2-(4-chloro-phenyl)-6-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:16]1[CH:36]=[CH:35][C:19]([O:20][C@@H:21]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1>C(COC)OC.O.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>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:16]1[CH:36]=[CH:35][C:19]([O:20][C@@H:21]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccco1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)Oc1ccc(Br)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 120.6 %

Procedure:
0.024 mmol of tetrakis(triphenylphosphine)palladium, 12.3 mmol of 2-furanboronic acid and 7.5 ml of 2 M sodium carbonate solution are added to a solution of 6.15 mmol of ethyl (2S)-2-(4-bromophenoxy)-4-phenylbutanoate in 25 ml of dimethoxyethane. The mixture is refluxed for 2 hours. After cooling to room temperature, the mixture is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate (Na2SO4) and then evaporated to dryness under vacuum. 2.6 g of a brown oil are obtained. This oil is chromatographed with a 9/1 heptane/ethyl acetate mixture as eluent. 1.5 g of an oil that crystallizes are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][O:22][CH3:23].C(OCC)(=O)C.CCCCCC>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][OH:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][O:22][CH3:23]
Reactant: COc1ccc(CO)cc1O
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COCCCOc1cc(CO)ccc1OC

Procedure:
7.7 g of 3-hydroxy-4-methoxy-benzyl alcohol, 10.35 g of potassium carbonate and 12.1 g of 1-bromo-3-methoxy-propane are stirred under reflux in 150 ml of acetone for 3 days. After evaporation of the solvent, water is added to the residue and extraction is carried out with ethyl acetate. After evaporation of the solvent the title compound is obtained from the organic extracts by means of FC (240 g of silica gel, dichloromethane/methanol=96:4): Rf (ethyl acetate/hexane=2:1)=0.31.
Reaction SMILES: O[C@@H:2]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[Si:19]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][NH:30][CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][N:30]([C@H:2]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[O:4])[CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COc1ccc(COC(=O)[C@@H](O)CC2CC2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(F)c1
Product: COc1ccc(COC(=O)[C@@H](CC2CC2)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3cccc(F)c3)C2)cc1
Yield: 91.4 %

Procedure:
The title compound was prepared from 200 mg (0.8 mmol) of 2-(S)-hydroxy-3-cyclopropyl propanoic acid, 4-(methoxy)benzyl ester (from EXAMPLE 21, Step B) and 321 mg (1.0 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-(3-fluorophenyl)pyrrolidine (from EXAMPLE 20, Step H) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 396 mg (91%) of the title compound: RF: 0.59 (4:1 a/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.01-0.14 (m, 81), 0.39-0.54 (m, 2H), 0.72 (m, 11H), 0-85 (s, 9H), 1.61-1.72 (m, 2H), 2.34 (m, 1H), 2.64 (br t, 1H), 2.75 (br t, 1H), 2.95-3.17 (m, 31), 3.38-3.60 (m, 3H), 3.82 (s, 3H), 5.13 (s, 3H), 6.85-7.00 (m, 5H), 7.18-7.36 (m, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21].C(Cl)(Cl)Cl.O>N1C=CC=CC=1>[C:20]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])(=[O:22])[CH3:21]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCC(OC(C)=O)C(=O)O
Reaction time: 12 h
Yield: 95.3 %

Procedure:
2-Hydroxyhexadecanoic acid (1 g) was dissolved in pyridine, and acetic anhydride (0.62 g) was added to the solution in an ice bath. After 12 hours, the reaction mixture was distributed into chloroform and water, and the chloroform layer was concentrated to give 2-acetoxyhexadecanoic acid (1.10 g). To 2-acetoxyhexadecanoic acid (0.50 g) dissolved in N,N-dimethylformamide (DMF) were added para-nitrophenol (0.22 g) and N,N'-dicyclohexylcarbodiimide (0.33 g), and the mixture was stirred for 8 hours. The reaction mixture was filtered, and 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (0.61 g) and triethylamine (2.0 ml) were added to the filtrate. The mixture was stirred for 12 hours.
Reaction SMILES: [CH3:1][N:2]([C@@H:11]([CH2:15][CH:16]=[CH2:17])[C:12]([OH:14])=O)[C:3](=[O:10])[C@@H:4]([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:18]([O:21][C@H:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[C@@H:24]([NH:33][CH2:34][C@@H:35]([OH:47])[C@@H:36]([NH2:46])[CH2:37][C:38]2[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40]([Cl:45])[CH:39]=2)[CH2:23]1)[CH:19]=[CH2:20]>>[CH2:18]([O:21][C@H:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[C@@H:24]([NH:33][CH2:34][C@@H:35]([OH:47])[C@@H:36]([NH:46][C:12](=[O:14])[C@@H:11]([N:2]([CH3:1])[C:3](=[O:10])[C@@H:4]([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH2:15][CH:16]=[CH2:17])[CH2:37][C:38]2[CH:39]=[C:40]([Cl:45])[CH:41]=[C:42]([Cl:44])[CH:43]=2)[CH2:23]1)[CH:19]=[CH2:20]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(Cl)cc(Cl)c2)c2cc(OC)ccc21
Reactant: C=CC[C@@H](C(=O)O)N(C)C(=O)[C@@H](C)CCCC
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(Cl)cc(Cl)c2)NC(=O)[C@H](CC=C)N(C)C(=O)[C@@H](C)CCCC)c2cc(OC)ccc21

Procedure:
Step DO (1): (S)-2-((S)-N,2-Dimethylhexanamido)pent-4-enoic acid (26.5 mg, 0.11 mmoles, diastereomer A from Preparation D) and (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol (47 mg, from Preparation BG) were coupled by a procedure analogous to Step DL (1) to afford 29.5 mg of (S)-N-((S)-1-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-dichloro-phenyl)-3-hydroxybutan-2-ylamino)-1-oxopent-4-en-2-yl)-N,2-dimethylhexan-amide as a clear oil. LC-MS Rt 2.25 min (method A), (M+H)+=674.2, 676; 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J=8.2, 1H) 7.18 (m, 1H) 7.09 (s, 1H) 7.06 (s, 1H) 6.94 (s, 1H) 6.84 (d, J=8.2, 1H) 6.37 (d, J=8.8, 1H) 5.95 (m, 1H) 5.58 (m, 1H) 5.30 (m, 1H) 5.18 (d, J=10.3, 1H) 5.10-4.97 (m, 3H) 4.77 (m, 1H) 4.18-4.05 (m, 3H) 3.81 (s, 1H) 3.80 (s, 3H) 3.46 (m, 1H) 3.13 (d of d, J=15, 2, 3.1, 1H) 3.01 (d of d, J=14.6, 3.6, 1H) 2.87 (s, 1H) 2.86-2.78 (m, 2H) 2.74-2.45 (m, 7H) 2.42-2.32 (m, 1H) 1.93 (m, 1H) 1.65-1.45 (m, 1H) 1.37-1.13 (m, 6H) 1.02 (d, J=7.0, 2H) 0.95 (d, J=7.0, 1H) 0.87 (m, 4H).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:26])([F:25])[C:18]1[N:23]=[CH:22][C:21](O)=[CH:20][N:19]=1.CCN(C(C)C)C(C)C.P(=O)(O)(O)O>C(Cl)Cl.O>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:21]1[CH:20]=[N:19][C:18]([C:17]([F:26])([F:25])[F:16])=[N:23][CH:22]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cnc(C(F)(F)F)nc1
Agent: O=P(O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Oc1cnc(C(F)(F)F)nc1)C(F)(F)F
Temperature: 4 °C
Reaction time: 2.5 h
Yield: 89.4 %

Procedure:
Triflic anhydride (13.9 g, 85 mmol) in dry DCM (70 mL) was added slowly to an ice-cold solution of 2-(trifluoromethyl)pyrimidin-5-ol (13.9, 85 mmol) (U.S. Pat. No. 4,558,039), DIPEA (16 mL, 93 mmol) and dry DCM (260 mL) at such a rate that the temperature was kept between 4° C. and 6° C. After the addition was complete, the solution was stirred for 2.5 h at 4° C. and then allowed to warm to RT. Water (50 mL) and 1M phosphoric acid (4.5 mL) were added and the phases were washed and separated. The organic phase was washed successively with water and saturated sodium bicarbonate, dried, filtered and carefully concentrated by rotary evaporation (pressure 300-400 mbar). The dark-red oil was purified by column chromatography with EtOAc-heptanes (1:8 through 1:4) as eluent to give 22.5 g (90%) of the title product as a colourless oil that crystallised in the cold. Alternatively, the product could be purified by distillation, b.p. 75-77° C./10 mbar.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][CH3:13])[C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2.[H][H]>[Pd].O1CCCC1>[OH:1][CH:2]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][CH3:13])[C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: [H][H]
Reactant: COCc1cccc(C=CC(O)c2ccccc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: COCc1cccc(CCC(O)c2ccccc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Yield: 77.1 %

Procedure:
35 mg of 10% w/w palladium-on-carbon were added to 15 ml of a tetrahydrofuran solution containing 111 mg (0.226 mmol) of N-[2-(3-hydroxy-3-phenyl-1-propenyl)-6-methoxymethylphenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 6), and the mixture was stirred vigorously for 15 hours in a stream of hydrogen. The reaction solution was then filtered with the help of a Celite (trade mark) filter aid, and the catalyst was washed with tetrahydrofuran. The filtrate and the washings were combined, and the solvent was removed from the combined solution by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 15 g of silica gel. Elution with a 4:1 by volume mixture of methylene chloride and ethyl acetate afforded 86 mg (yield 77%) of the title compound as crystals, melting at 143.5°-146° C. (after recrystallization from a mixture of methanol and hexane).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:20])=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[C:10]([C:21]([OH:23])=O)=[C:9]1[CH:24]([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][NH2:32]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:20])=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[C:10]([C:21]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([F:36])=[C:28]([F:27])[CH:29]=2)=[O:23])=[C:9]1[CH:24]([CH3:25])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: CC(C)c1c(C(=O)O)c2cc(F)c([N+](=O)[O-])cc2n1Cc1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c([N+](=O)[O-])cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylic acid (Compound 170) and 3,4-difluorobenzylamine by General Procedure C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(Cl)(Cl)=O>C(O)CCC>[CH2:13]([O:14][C:13](=[O:15])[C@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[NH2:1])[CH2:2][CH2:3][CH3:4]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: CCCCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Temperature: 100 °C
Yield: 181.9 %

Procedure:
L-Tryptophane (5 g; 24.5 mmol) and thionyl chloride (73.5 mmol; 5.3 ml) were dissolved in n-butanol (80 ml) and stirred at 100° C. over night. The product 5 precipitated after cooling to room temperature, was filtered off and washed with ice cold butanol and petrol ether. The product was dried at the oil pump, yielding 5.8 g of 5 (91%).
Reaction SMILES: [CH:1]1([C:6](=[CH2:19])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=2[Cl:18])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>S(=O)(=O)(O)O>[Cl:17][C:11]1[C:10]([Cl:18])=[C:9]2[C:14]([CH2:19][CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:7]2=[O:8])=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)C1CCCC1
Agent: O=S(=O)(O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
4-(2-Cyclopentyl-2-methyleneacetyl)-2,3-dichloroanisole (33.3 g.) is dissolved in 98% sulfuric acid (150 ml.) and stirred at 20° C. for 1.5 hours. The solution then is added dropwise with stirring to ice water. The aqueous phase is decanted from the gummy product and fresh water is added. After 20 hours the gum solidifies and is crystallized from hexane-benzene (3:1) to obtain 6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-methoxy-1H-inden-1-one, m.p. 116°-117° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Reactant: O=C(Cl)c1ccncc1
Agent: [Ag]
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)c1ccncc1

Procedure:
3.48 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1yl]-2-triphenylphosphoranylideneacetic acid allyl ester are converted with isonicotinic acid chloride into the title compound analogously to Example 1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([C@@H:8]2[CH2:13][CH2:12][C@H:11](O)[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C([N:17](CC)CC)C.C(Cl)Cl.CS(Cl)(=O)=O.CN(C=O)C.[N-]=[N+]=[N-].[Na+].O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[I:1][C:2]1[CH:3]=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH2:17])[CH2:10][CH2:9]2)[C:6]=1[CH3:7]
Reactant: Cc1c(I)cnn1[C@H]1CC[C@@H](O)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1c(I)cnn1[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cis-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)cyclohexanol (400.0 mg, 1.306 mmol), triethylamine (0.5463 mL, 3.920 mmol) and DCM (10 mL, 200 mmol) was added methanesulfonyl chloride (0.2022 mL, 2.613 mmol), and the reaction was stirred at rt for 2 h. The material was extracted with DCM and water, which was titrated to pH=5. The organic layer was concentrated in vacuo, redissolved in DMF (5 mL, 60 mmol), and sodium azide (169.9 mg, 2.613 mmol) was added. The mixture was heated to 90° C. for 3 h. The material was extracted with EtOAc, and washed with water (2×). The organic layer was concentrated in vacuo, redissolved in 1,4-dioxane (5 mL, 60 mmol), and PPh3 (514.0 mg, 1.960 mmol) was added. The mixture was heated to 70° C. for 3 h. The solvent was removed in vacuo, and the material was extracted with DCM and water, which was titrated to pH=2. The organic layer was discarded, more DCM was added, and the aqueous layer was titrated to pH=9. The organic layer was concentrated in vacuo to afford the title compound as a light yellow solid. MS (ES+): m/z=306.04 (100) [MH+]. HPLC: tR=0.89 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([P:14](=[O:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[I:36]I.Cl>C1COCC1.C1COCC1.CCCCCCC.C(OCC)(=O)C>[I:36][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][C:3]=1[P:14](=[O:27])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(c1)oc1ccccc12
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(oc3ccccc32)c1I
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
9.8 g of (dibenzofuran-3-yl)-diphenyl-phosphine oxide in 100 ml of THF are admixed with 13.3 ml of a 2M solution of lithium diisopropylamide in THF/n-heptane and stirred for a further 10 minutes at -78° C. A solution of 7.9 g of iodine in 30 ml of THF is added at -76° C. Subsequently the mixture is hydrolyzed with 2N HCl, ethyl acetate is added, the solution is washed with sodium thiosulphate solution, water and saturated NaCl solution, dried with MgSO4 and concentrated. 12.7 g (98% of theoretical) of crude product remain.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18]>C1COCC1.CCCCCC>[Cl:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: Clc1cc(Br)c2[nH]ncc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc2cn[nH]c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
463 mg (2 mmol) of 7-bromo-5-chloro-1H-indazol were dissolved in 12 ml THF. The so-lution was cooled to −78° C. under argon. 3.75 ml (6 mmol) of a 1.6 M butyl lithium solution in hexane were added slowly within 10 min. The reaction mixture was warmed to 5° C. and stirred for 30 min at this temperature. A suspension was obtained, which was cooled to −78° C. Solid carbon dioxide was added and the reaction mixture was warmed to rt. At 10° C. the suspension became a clear solution. The solvent was evaporated and the residue was treated with water and diethyl ether. The aqueous layer was extracted once with diethyl ether, acidified with 1N aqueous HCl solution. A white solid precipitated, which was filtered off and washed with water. The solid was suspended in diethyl ether/heptane in order to remove pentanoic acid. 130 mg (33%) of 5-chloro-1H-indazole-7-carboxylic acid were obtained as a white solid after filtration and drying. MS (ISP) 195.1 (M−H)−.
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[N:20]2)(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[CH3:25][C:21]1[CH:22]=[C:23]([CH3:24])[N:19]([C:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=2[OH:11])[N:20]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ccc2-n2nc(C)cc2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2nc(C)cc2C)c(O)c1
Yield: 58.5 %

Procedure:
To 199.6 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenyl 4-methylbenzene sulfonate was added a solution in which 314 mg of potassium hydroxide was dissolved in 4 ml of ethanol and 4 ml of water, and the mixture was heated at reflux for 1 hour. To the reaction mixture was added 20 ml of water, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=4:1), and after the desired fraction was dissolved in 1,4-dioxane, it was lyophilized to yield 66.2 mg of the title compound.