Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.[OH-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[CH:3]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.50 g (2.83 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane were cooled with an ice/ethanol bath and combined with 0.30 mL (2.68 mmol) 2,3-dihydro-1H-indole. 2.7 mL (2.7 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 2 h with cooling and for 1 h at RT. Then 50 mL of an aqueous saturated sodium hydrogen carbonate solution were added. After 10 min stirring the organic phases was separated off and washed with water and 1 M hydrochloric acid. The organic phases was dried on magnesium sulphate, filtered and evaporated down i.vac.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:31][C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=3)[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:31][C@@H:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:45][CH:44]=3)=[CH:17][CH:18]=2)[C:24]([OH:26])=[O:25])=[O:43])=[CH:34][CH:35]=1)([CH3:40])([CH3:41])[CH3:42]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)O)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A crude solution of (S)-4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl 4-(heptyloxy)benzoate in DCM (1 mL) was treated with TFA (0.15 mL) and stirred overnight at 30° C. The solvent was evaporated and the residue was purified by preparative HPLC to give 12.3 mg (33%) of (S)-2-(4-(tert-butyl)benzamido)-3-(4-((4-(heptyloxy)benzoyl)oxy)phenyl)propanoic acid 57. LCMS-ESI (m/z) calculated for C34H41NO6: 559; found 560 [M+H]+, tR=12.14 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 8.65 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.9 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 4.63 (ddd, J=10.8, 8.2, 4.4 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.22 (dd, J=13.9, 4.3 Hz, 1H), 3.10 (dd, J=13.8, 10.8 Hz, 1H), 1.81-1.66 (m, 2H), 1.50-1.20 (m, 8H), 1.29 (s, 9H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([Br:16])=[C:8]([NH2:15])[C:9]=2[N+:12]([O-:14])=[O:13])[CH2:4]1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.C(N(C(C)C)CC)(C)C.CCOC(C)=O>CN(C=O)C.CO>[NH2:15][C:8]1[C:9]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5](=[CH:6][C:7]=1[Br:16])[CH2:4][CH:3]([N:2]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:11]2
Reactant: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(N)C2
Reactant: BrCCCCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(N1CCCCC1)C2
Temperature: 50 °C
Yield: 47 %

Procedure:
A mixture of 2,5-diamino-6-bromo-4-nitroindane hydrochloride (1.5 g, 5 mmol), 1,5-dibromopentane (1.4 g, 6 mmol) and diisopropylethylamine (1.3 g, 10 mmol) in DMF (100 mL) was heated at 50° C. for 24 h. The solvent was evaporated and the residue taken up in methylene chloride:water. The aqueous layer was basified with 2N NaOH and back extracted. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a syrup. The purified product (0.8 g) was obtained from column chromatography (4:1 EtOAc:methanol).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)[CH2:6]1)=[N+]=[N-].[H][H]>C1COCC1.CO.[Pd]>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)[CH2:6]1
Reactant: [H][H]
Reactant: CN1CCc2cc(N3C[C@@H](CN=[N+]=[N-])OC3=O)ccc2C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCc2cc(N3C[C@H](CN)OC3=O)ccc2C1

Procedure:
184 mg (0.6 mmol) (S)-5-azidomethyl-3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-oxazolidin-2-one are dissolved in a mixture of 2 ml THF and 10 ml of methanol, combined with 50 mg palladium/charcoal (5%) and hydrogenated for two hours at 3 bar hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated to dryness i. vac.
Reaction SMILES: C(N(CC)CC)C.C([Mg]Cl)(C)C.Br[C:14]1[C:15]([O:22][CH3:23])=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].ClC1C(C)=C([Mg]Cl)C(OC)=NC=1.[CH3:36][O:37][C:38]1[C:45]([O:46][CH3:47])=[C:44]([O:48][CH3:49])[CH:43]=[C:42]([CH3:50])[C:39]=1[CH:40]=[O:41]>O1CCCC1.O>[CH3:36][O:37][C:38]1[C:45]([O:46][CH3:47])=[C:44]([O:48][CH3:49])[CH:43]=[C:42]([CH3:50])[C:39]=1[CH:40]([C:14]1[C:15]([O:22][CH3:23])=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20])[OH:41]
Reactant: COc1ncc(Cl)c(C)c1Br
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: CC(C)[Mg]Cl
Agent: COc1ncc(Cl)c(C)c1[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C)c(C(O)c2c(OC)ncc(Cl)c2C)c(OC)c1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
4 ml of tetrahydrofuran and 0.62 ml (4.4 mmol) of triethylamine were added to 2.2 ml (4.4 mmol) of isopropylmagnesium chloride (2.0 mol/l tetrahydrofuran solution), the mixture was cooled to 0° C., and a solution having 1.0 g (4.2 mmol) of 3-bromo-5-chloro-2-methoxy-4-methylpyridine dissolved in 5 ml of tetrahydrofuran was dropwise added, followed by stirring for 3 hours to prepare 5-chloro-2-methoxy-4-methyl-3-pyridylmagnesium chloride. A solution having 0.89 g (4.2 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 5 ml of tetrahydrofuran was dropwise added to the reaction solution, followed by stirring for 1 hour, and then the temperature was increased to room temperature, followed by stirring further for 1 hour. Water was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1.1 g (yield: 70%) of (2,3,4-trimethoxy-6-methylphenyl)(5-chloro-2-methoxy-4-methyl-3-pyridyl)methanol (pale yellow oily substance).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH2:11])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19](=S)=[S:20]>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:19](=[S:20])[NH:11][CH:10]=2)[CH:9]=1
Reactant: S=C=S
Reactant: NCc1ccc(F)cn1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1ccc2c[nH]c(=S)n2c1
Temperature: 75 °C
Yield: 33.5 %

Procedure:
In a round-bottomed flask, (5-fluoropyridin-2-yl)methylamine dihydrochloride (600 mg, 3.0 mmol) was suspended in methanol (16 ml). Triethylamine (1.4 ml, 10.0 mmol) was added followed by carbon disulfide (1.4 ml, 23.2 mmol). The reaction mixture was stirred at reflux (oil bath temperature=75° C.) overnight then cooled to room temperature and then concentrated. The residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane then the organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 169 mg (33%) of 6-fluoro-2H-imidazo[1,5-a]pyridine-3-thione as an orange solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.47 (br. s., 1H), 8.04 (dd, J=4.9, 1.1 Hz, 1H), 7.43-7.56 (m, 2H), 6.88 (ddd, J=10.0, 7.9, 2.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:40])[CH2:20][NH:21][C:22]([CH3:39])([CH3:38])[CH2:23][CH2:24][N:25]2[CH:29]=[N:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[N:26]2)=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:40])[CH2:20][NH:21][C:22]([CH3:39])([CH3:38])[CH2:23][CH2:24][N:25]2[CH:29]=[N:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[N:26]2)=[CH:15][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(O)CNC(C)(C)CCn2cnc(-c3ccc(OC)cc3)n2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2ncn(CCC(C)(C)NCC(O)c3ccc(OCc4ccccc4)c(CO)c3)n2)cc1

Procedure:
7.3 g of methyl 2-benzyloxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-benzoate are placed in 100 mL tetrahydrofuran and reduced with a total of 6.8 g of calcium chloride dissolved in ethanol and 4.6 g of sodium borohydride as described for Example 1c. The product is obtained after purification by column chromatography (CHCl3/MeOH/NH3=90/10/0.5) and subsequent recrystallisation from acetonitrile.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([CH2:18][F:19])[CH:15]=[C:16](O)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.O>C(Cl)Cl.CCCCCC>[CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([CH2:18][F:19])[CH:15]=[C:16]([Cl:23])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(CF)nc2nc(SCc3ccccc3)nn12
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: FCc1cc(Cl)n2nc(SCc3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 17.0 g (58.6 mmol) of 2-benzylthio-5-fluoromethyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine and 100 ml of phosphorus oxychloride was heated at reflux for three hours and was then concentrated by simple distillation using a water aspirator to reduce the pressure to obtain a dark, viscous oil. This was dissolved in 300 ml of methylene chloride and treated cautiously with stirring with 200 ml of water. The mixture was stirred vigorously for 30 min. at ambient temperature and then allowed to separate into phases. The organic phase was separated, washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure to obtain a dark oil. This solidified on trituration in hexane containing a little methylene chloride to yield 12.2 g (67 percent of theory) of the title compound as a tan solid melting at 81°-86° C.
Reaction SMILES: C(O[CH:4](O)[C:5]([C:7]1[CH:8]=[C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6])C.[NH2:24][C:25]([CH3:42])([CH3:41])[CH2:26][CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.[BH4-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(N(CC)CC)C.C(OCC)(=O)C>[C:17]1([S:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:5]([OH:6])[CH2:4][NH:24][C:25]([CH3:42])([CH3:41])[CH2:26][CH2:27][N:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH:12]=[CH:11][CH:10]=2)(=[O:15])=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(O)C(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)N)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(ccn2CCC(C)(C)NCC(O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 80 °C

Procedure:
154 mg (0.46 mmol) N-[3-(2-ethoxy-2-hydroxyacetyl)-phenyl]-benzenesulphonamide (Component I) and 125 mg (0.48 mmol) methyl 1-(3-amino-3-methyl-butyl)-indole-5-carboxylate (Component IV) are dissolved in 10 ml of ethanol and combined with 4 drops of triethylamine. The reaction solution is heated to 80° C. for 17 hours. Then it is cooled to 0° C. and over a period of 2.5 hours 140 mg (3.7 mmol) sodium borohydride are added batchwise. The mixture is stirred for another hour at 0° C. and the reaction solution is then poured into a mixture of 20 ml of saturated aqueous potassium carbonate solution and 50 ml of ethyl acetate. After separation of the organic phase the aqueous phase is extracted with ethyl acetate. The combined organic phases are with washed saturated aqueous saline solution and dried on sodium sulphate. Then the solvent is eliminated in vacuo and the residue is chromatographed on silica gel (DCM/methanol=100:0:0→9:1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[Na+].Cl>C(N)(C)C.CC(C)=O.C(OCC)C>[ClH:1].[CH:15]([NH:6][CH2:2][CH2:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:20])[CH3:16]
Reactant: O=C1c2ccccc2C(OCCCl)N1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)N
Solvent: O
Solvent: CCOCC
Product: CC(C)NCCOC1c2ccccc2C(=O)N1c1ccccc1

Procedure:
A solution of 3-(2-chloroethoxy)-2-phenyl-isoindolin-1-one in isopropylamine (120cc.) is heated in an autoclave at 120°C. for 24 hours. After cooling, the reaction mixture is poured into water (200 cc.) and 4N sodium hydroxide solution (16 cc.). The alkaline solution obtained is extracted with diethyl ether (250 cc.). The organic solution is washed with water (3 × 50 cc.) and is then extracted with 4N hydrochloric acid (18 cc.). The acid solution obtained is rendered alkaline by adding 4N sodium hydroxide solution (20 cc.) and the oily product which separates out is extracted with diethyl ether (2 × 100 cc.). The organic extracts are then dried over sodium sulphate and concentrated to dryness under reduced pressure. A product (14.2 g.), which melts at about 85°C., is obtained and is dissolved in acetone (150 cc.). A 4.03N solution of hydrogen chloride in diethyl ether (11.3 cc.) is added to the resulting solution. The product which crystallises is filtered off and then washed with acetone (10 cc.). After drying, 3-(2-isopropylaminoethoxy)-2-phenyl-isoindolin-1-one hydrochloride (11.3 g.), which melts at 184° C., is obtained.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[CH:28]=[N:27]4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[CH:28]=[N:27]4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-n3ncc4cc(Cl)ccc43)cnc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CCN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-n4ncc5cc(Cl)ccc54)nc23)C2CC2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
In a round-bottomed flask, 2-(5-chloro-indazol-1-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (51 mg, 0.08 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.25 ml, 3.24 mmol) was added. The yellow reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.5 ml) and ethylenediamine (0.33 ml, 4.89 mmol) was added. The reaction was stirred at room temperature for 1.5 h then quenched with water and extracted with EtOAc (2×30 ml). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc) followed by trituration with EtOAc/hexanes (1:1) to provide 22 mg (52%) of 2-(5-chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow solid. MS: (M+H)+=503; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.01 (br. s., 1H), 9.10 (s, 1H), 8.94 (dd, J=8.9, 5.1 Hz, 1H), 8.54 (d, J=0.8 Hz, 1H), 8.51 (d, J=6.8 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.07 (d, J=1.9 Hz, 1H), 7.56 (t, J=6.6 Hz, 1H), 4.92-5.02 (m, 1H), 3.70-4.06 (m, 2H), 3.09-3.68 (m, 3H), 1.50-2.08 (m, 4H), 1.20-1.39 (m, 1H), 0.31-0.61 (m, 4H).
Reaction SMILES: C([O:5][C:6]([C:8]1([N:18]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[CH3:19])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])(C)(C)C.[O:27]1CCOC[CH2:28]1>Cl>[CH2:23]([O:22][C:20]([N:18]([CH3:19])[C:8]1([C:6]([OH:5])=[O:7])[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([O:27][CH3:28])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:21])[CH:24]([CH3:25])[CH3:26]
Reactant: C1COCCO1
Reactant: CC(C)COC(=O)N(C)C1(C(=O)OC(C)(C)C)CCc2ccccc2C1
Agent: Cl
Product: COc1cccc2c1CC(C(=O)O)(N(C)C(=O)OCC(C)C)CC2
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
The t-butyl ester from Example 33E was dissolved in 4 N HCl in dioxane (10 mL) and the resulting mixture was stirred at r.t for 16 h and at 60° C. for 1.5 h. The volatiles were removed to give the titled acid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][C@@:17]([CH3:24])([O:22][CH3:23])[C:18]([F:21])([F:20])[F:19])[C:13]([NH2:25])=[C:12]([F:26])[CH:11]=2)[CH2:5][S@@:4](=[O:27])[CH2:3]1.[C:28]([C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH:35]=O)([CH3:31])([CH3:30])[CH3:29]>>[NH2:25][C:13]1[C:14]([O:16][C@@:17]([CH3:24])([O:22][CH3:23])[C:18]([F:21])([F:19])[F:20])=[CH:15][C:10]([CH2:9][C@H:6]2[C@H:7]([OH:8])[C@@H:2]([NH:1][CH2:35][C:34]3[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:33]=3)[CH2:3][S@:4](=[O:27])[CH2:5]2)=[CH:11][C:12]=1[F:26]
Reactant: CO[C@](C)(Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](N)[C@H]2O)cc(F)c1N)C(F)(F)F
Reactant: COc1cc(C=O)cc(C(C)(C)C)c1
Product: COc1cc(CN[C@H]2C[S@](=O)C[C@@H](Cc3cc(F)c(N)c(O[C@@](C)(OC)C(F)(F)F)c3)[C@@H]2O)cc(C(C)(C)C)c1

Procedure:
The title compound was prepared in an analogous manner as described for example 48g starting from (1R,3R,4S,5S)-3-amino-5-[4-amino-3-fluoro-5-((R)-2,2,2-trifluoro-1-methoxy-methyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol (example 48f) and 3-tert-butyl-5-methoxy-benzaldehyde and was obtained after purification by column chromatography on silica gel with (EtOAc/5% MeOH) 70-0% hexane as a colorless foam: TLC (AcOEt-MeOH 19:1) Rf=0.43; HPLC RtH1=2.55 min; ESIMS [M+H]+=591; 1H NMR (600 MHz, DMSO-d6): δ 6.92 (s, 1H), 6.75 (s, 2H), 6.72 (s, 1H), 6.67 (d, 3H), 5.01 (br s, 1H), 4.60 (br s, 2H), 3.77-3.68 (m, 3H), 3.73 (s, 3H), 3.61 (d, 1H), 3.30 (s 3H), 3.15 (m, 1H), 3.10 (m, 2H), 2.96 (m, 1H), 2.70 (m, 1H), 2.50-2.25 (m, 5H), 1.24 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>O1CCCC1.C(O)(=O)C>[CH:9]1([CH2:15][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OC[C@H]1CCCNC1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC[C@H]1CCCN(CC2CCCCC2)C1
Reaction time: 21 h
Yield: 59.9 %

Procedure:
To a solution of 900 mg of (3S)-3-piperidylmethanol in 60 ml of tetrahydrofuran, 1.05 g of cyclohexanecarbaldehyde, 0.54 ml of acetic acid and 2.5 g of sodium triacetoxyborohydride were successively added at room temperature by the order stated, followed by 21 hours' stirring at the same temperature. The reaction liquid was rendered acidic with 1N hydrochloric acid and washed with chloroform. The aqueous layer was rendered basic with 4N aqueous sodium hydroxide solution, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 990 mg of the title compound was obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: COc1cccc(C(O)c2cccc(F)c2)c1
Product: COc1cccc(C(OC(=O)O[C@H]2CN3CCC2CC3)c2cccc(F)c2)c1

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-(3-methoxy-phenyl)-methanol.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Br>CC#N>[CH3:17][O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][NH:16][C@@H:14]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH3:15]
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCN[C@H](C)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a suspension of K2CO3 (1.5 eq.) and (R)-1-(4-chloro-phenyl)-ethylamine (0.9 eq.) in MeCN was added 4-bromo-butyric acid methyl ester (1 eq.) and KI (0.1 eq.). The reaction was stirred for 15 h at 20° C., then heated to reflux until completion. The crude was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 99/1 to 90/10) to afford 4-[(R)-1-(4-chloro-phenyl)-ethylamino]-butyric acid methyl ester.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8](C(OC(C)(C)C)=O)[C@@H:9]([C:20]([NH:22][C@H:23]([C:39]([O:41][CH3:42])=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[ClH:50].C(OCC)C>C(Cl)Cl.C(OCC)C>[NH2:8][C@@H:9]([C:20]([NH:22][C@H:23]([C:39]([O:41][CH3:42])=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[ClH:50]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
150 ml TFA are added to 30 g BOC-(D)Trp-Lys(Z)-OMe in 150 ml methylene chloride pre-cooled to 0° C. The whole is stirred for 40 minutes at room-temperature and then added to 30 ml HCl/ethyl-ether (~5 N) in 4 l ethyl-ether. After thorough stirring the precipitate is filtered off, washed with ethyl-ether and dried to yield the title compound: