Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:18](Cl)=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH:13]1([C:18]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)C1CCCC1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1cccc2oc(C3CCCC3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
To a suspension of 2-amino-3-hydroxybenzoic acid hydrobromide (300 mg, 1.28 mmol) in dichloromethane (8 mL) was added cyclopentane carbonyl chloride (0.16 mL, 1.28 mmol). The resulting reaction mixture was stirred at room temperature for 10 min, then triethylamine (0.71 mL, 5.13 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was diluted in dichloromethane (30 mL) and quenched with aqueous 2 N HCl (10 mL) until the solution reached pH 1. The aqueous layer was further extracted with dichloromethane (2×30 mL). The organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to an orange solid. The amide product was directly re-dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (296 mg, 1.56 mmol). The reaction mixture was then heated to reflux for 3 h. The reaction was cooled to room temperature and the toluene was evaporated. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford 2-cyclopentylbenzoxazole-4-carboxylic acid (179 mg, 75%) as a pale orange solid: 1H NMR (500 MHz, DMSO-d6) δ 7.85-7.72 (m, 2H), 7.39-7.29 (m, 1H), 2.05-1.50 (m, 9H); MS (ESI+) m/z 232 (M+H).
Reaction SMILES: [CH2:1]([C:8]([CH2:10][CH2:11][CH3:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH2:14][CH3:15].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C1C=CC=CC=1.CO.O>[CH2:13]([NH:16][CH:8]([CH2:10][CH2:11][CH3:12])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][CH3:15]
Reactant: CCCC(=O)Cc1ccccc1
Reactant: CCCN
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: CCCNC(CCC)Cc1ccccc1
Reaction time: 6 h

Procedure:
11.0 g (0.068 mole) of benzyl-propyl-ketone are dissolved in 110 ml of benzene, whereupon 8.0 g (0.135 mole) of n-propyl-amine and 22.6 g (0.2 mole) of anhydrous calcium chloride are added to the solution. The reaction mixture is stirred at 40°-50° C. for 6 hours, then filtered and evaporated. The crude ketimine thus obtained is dissolved in 120 ml of methanol, whereupon 6.4 g (0.17 mole) of sodium borohydride are added. The reaction mixture is allowed to stand, whereupon it is poured into 500 ml of water and extracted five times with 100 ml of benzene each. The benzene solution is dried and evaporated. The crude N-propyl-1-phenyl-2-pentylamine thus obtained is purified by distillation in vacuo. B.p.: 112°-120° C./7 Hgmm, n20D =1.5030.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[O:24][CH3:25].CC(OC(C)=O)=O.CCN(CC)CC>O.CCOC(C)=O>[F:15][C:16]1[CH:23]=[CH:22][C:19](/[CH:20]=[C:11](\[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)/[C:12]([OH:14])=[O:13])=[CH:18][C:17]=1[O:24][CH3:25]
Reactant: CC(C)Oc1ccc(CC(=O)O)cc1
Reactant: COc1cc(C=O)ccc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(/C=C(/C(=O)O)c2ccc(OC(C)C)cc2)ccc1F
Temperature: 25 °C
Yield: 65.2 %

Procedure:
2-(4-isopropoxyphenyl)acetic acid (3.97 g, 20.44 mmol), 4-fluoro-3-methoxybenzaldehyde (3.15 g, 20.44 mmol), Ac2O (3.47 ml, 36.8 mmol), and Et3N (1.994 ml, 14.31 mmol) were heated to 110° C. for 16 h. The reaction was cooled down to rt and diluted with water and EtOAc. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 10-20% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give (E)-3-(4-fluoro-3-methoxyphenyl)-2-(4-isopropoxyphenyl)acrylic acid (4.4 g, 65% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.85 (s, 1H), 7.22-7.16 (m, 2H), 6.98-6.91 (m, 3H), 6.82 (ddd, J=8.3, 4.6, 2.1 Hz, 1H), 6.63 (dd, J=8.5, 2.0 Hz, 1H), 4.64-4.54 (m, 1H), 3.51 (s, 3H), 1.39-1.35 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[N:29]1C=CC=CC=1.N1C(F)=NC(F)=NC=1F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:23]([CH3:28])([CH3:27])[C:24]([NH2:29])=[O:25])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: CC(C)(C(=O)O)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Agent: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Product: CC(C)(C(N)=O)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Reaction time: 1 h

Procedure:
(g) 2-(4-(1-(4-Fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropanoic acid (50 mg, 0.13 mmol) was dissolved in 5 mL DCM, 32 uL pyridine, and treated with 27 uL cyanuric fluoride. After 1 h, the reaction was extracted from NaHCO3 with EtOAc×3. The combined organic layers were dried over MgSO4, filtered, concentrated and taken up in 2 mL NMP and treated with triethylamine (100 uL) and NH4Cl (50 mg). The reaction was purified by HPLC to give 23 mg of 2-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropanamide. (M+H)+=382.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C1C=NC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[CH3:68][C:69]1[S:70][C:71]([CH2:74][N:75]2[C:80]3[CH:81]=[C:82]([C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)[S:83][C:79]=3[C:78](=[O:90])[N:77]([CH:91]3[CH2:96][CH2:95][NH:94][CH2:93][CH2:92]3)[C:76]2=[O:97])=[CH:72][N:73]=1>CCN(C(C)C)C(C)C>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:94]4[CH2:95][CH2:96][CH:91]([N:77]5[C:78](=[O:90])[C:79]6[S:83][C:82]([C:84]7[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=7)=[CH:81][C:80]=6[N:75]([CH2:74][C:71]6[S:70][C:69]([CH3:68])=[N:73][CH:72]=6)[C:76]5=[O:97])[CH2:92][CH2:93]4)=[O:22])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cnc(C)s5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (199 mg; compound C10), TOTU (213 mg) and HOAT (102 mg) in DIPEA (259 mg) is stirred for 50 min at RT. Subsequently, 1-[(2-methyl-1,3-thiazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (276 mg; compound B44) is added and the reaction mixture is stirred for additional 60 min at RT. The solvent is removed under reduced pressure and to the resulting residue DCM (15 ml) and saturated aqueous sodium bicarbonate solution (3 ml) are added. The organic phase is separated and the aqueous phase is extracted with DCM (10 ml). The combined organic phases are applied to a phase separator, dried over magnesium sulfate and the solvent is removed under reduced pressure to give the crude title compound. The residue is first purified by flash chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)]. After a second purification step applying preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluent: EtOAc/triethylamine, 97/3 (v/v)] the title compound is obtained as a solid.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28]([OH:30])=O)=[C:16]2[CH2:15]1.N>CN(C)C=O>[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28]([NH2:3])=[O:30])=[C:16]2[CH2:15]1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2sccc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2sccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
11.5 g (71 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 17 g (64.6 mmol) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-7-carboxylic acid (EP 285 837 A1)in 100 ml of N,N-dimethylformamide. The resulting pale brown solution was heated to 50° during 45 minutes. Subsequently, the solution was cooled to room temperature and 20 ml of aqueous ammonia solution were added dropwise thereto. After stirring for a further 30 minutes the reaction mixture was poured into 100 ml of ice-water and the resulting precipitate was filtered off and rinsed with water, ethanol and subsequently with ether. After drying at 70°/10 Torr there were obtained 15 g (89%) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxamide as colourless crystals of m.p. >250°.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](CC#C)[CH2:9]2)=[CH:4][CH:3]=1.OC1C=C2C(CCN(CC3CC3)C2)=CC=1.C(N(C)C(Cl)=O)C.N1(C(Cl)=O)CCCC1.N1(C(Cl)=O)CCCCC1.N1(C(Cl)=O)CCOCC1>CC#N>[CH2:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH2:6][CH2:7][NH:8]1
Reactant: C#CCN1CCc2ccc(O)cc2C1
Agent: CCN(C)C(=O)Cl
Agent: O=C(Cl)N1CCCC1
Agent: O=C(Cl)N1CCCCC1
Solvent: CC#N
Product: c1ccc2c(c1)CCNC2

Procedure:
Finally, 7-Hydroxy-N-propargyl-1,2,3,4-tetrahydroisoquinoline (8) and 7-Hydroxy-N-cyclopropylmethyl-1,2,3,4-tetrahydroisoquinoline (9), were added in a solution of N,N-dialkylcarbamyl chloride analogous compound (R2-CO—Cl) (10a-d) in CH3CN, wherein R2 represents, respectively, N-Ethyl-N-methyl amino, 1-Pyrrolidyl, 1-Piperidinyl or 1-Morpholinyl; said R2 possesses a structure of formula (IV), (V), (VI) or (VII), respectively; as such, analogous compound (R2-CO—Cl) (10a-d) were N-ethyl-N-methyl-carbamoyl chloride (10a), pyrrolidine carbonyl chloride (10b), piperidinyl carbonyl chloride (10c) and morpholine carbonyl chloride (10d), respectively, and after step (f), obtained 1,2,3,4-tetrahydroisoquinoline derivatives 11a-d and 12a-d respectively. Above-mentioned N-ethyl-N-methyl-carbamoyl chloride (10a), pyrrolidine carbonyl chloride (10b), piperidine carbonyl chloride (10c) and morpholine carbonyl chloride (10d), were commercially unavailable, but could be synthesized via conventional method as described in reference (1), using a solution of phosgene in toluene to give 10a-d.
Reaction SMILES: B(Br)(Br)Br.[O:5]=[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)=[O:18].C(=O)([O-])O.[Na+]>ClCCl>[O:5]=[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:18]
Reactant: COc1ccc(NC(=O)Nn2cnc3ccccc3c2=O)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1)Nn1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.0 molar solution of boron tribromide (6.45 mL, 6.45 mmol BBr3) is added dropwise to a mixture of 1-(3,4-dihydro-4-oxo-3-quinazolinyl)-3-(p-methoxyphenyl)urea (1.0 g, 3.22 mmol) in dichloromethane under a nitrogen atmosphere. The reaction mixture is stirred overnight at room temperature, adjusted to about pH 8 with saturated sodium hydrogen carbonate solution, stirred for 2 hours, washed with water and filtered. The filter cake is dried, triturated with hot acetone, filtered and dried to give the title product as a white solid, 0.42 g, mp 220°-223° C., which is identified by 1HNMR spectral analysis.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH:9]1[CH2:21][C:22](OC)=[O:23])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[CH2:21][CH2:22][OH:23]
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C)C(CCO)C1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a stirred solution of 2-methoxycarbonylmethylpiperazine-1,4-dicarboxylic acid di-tert-butyl ester (662 mg, 1.85 mmol) in anhydrous THF (10 mL) at 0° C. was slowly added a 1M solution of LiAlH4 in THF (5.7 mL, 5.70 mmol). The stirred reaction mixture was allowed to warm to room temperature over a period of 15 minutes before being refluxed for 2 hours. After this time the reaction mixture was cooled to 0° C. and cautiously quenched by the dropwise addition of 1.0M aqueous NaOH solution until the effervescing ceased. The resulting gel was diluted with THF (50 mL) and the solids filtered off. The filtrate was concentrated in vacuo to afford 2-(1,4-dimethylpiperazin-2-yl)ethanol (191 mg, 65%) as a colourless oil.
Reaction SMILES: O[CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]1([CH3:15])[O:12][CH:11]([CH2:13][OH:14])[CH2:10][O:9]1.S(C1C=CC(C)=CC=1)(OC)(=O)=O.[OH-:28].[Na+]>O.CC(C)=O>[CH3:2][C:3]([CH2:5][OH:6])([OH:4])[C:8]([CH3:15])([CH3:7])[OH:28].[CH3:7][C:8]1([CH3:15])[O:12][CH:11]([CH2:13][OH:14])[CH2:10][O:9]1
Reactant: [OH-]
Reactant: OCC(O)CO
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Solvent: CC1(C)OCC(CO)O1
Solvent: CC(C)=O
Product: CC(C)(O)C(C)(O)CO

Procedure:
Trimethyl glycerol was prepared from glycerol through a ketal glecerol derivative, solketal (1,2-isopropylidene glycerol) as shown in FIG. 2. Solketal starting material was prepared by reacting 1 g glycerol with 2 ml acetone and 1 g Dowex 50W strong cation exchange resin (Dow Chemical Co., Midland, Mich.) at 60° C. for 1 hour. The resultant solketal (3 mmol) was reacted with 3 mmol methyl tosylate (as prepared in Example 1) in 3 mmol NaOH with mL water in a small scale vessel for 2 hours at 70° C., producing methyl solketal. Hydrolysis of the methyl solketal was effected by reaction with Dowex 50W strong cation exchange resin (½″) in 4 ml methanol for 2 hours at 70° C., producing 1-methyl glycerol. The 1-methyl glycerol produced from the hydrolysis was reacted with 2 molar equivalents of methyl tosylate in aqueous NaOH for 2 hours at 70° C., yielding 1,2,3-trimethoxy glycerol ether.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:19].[K+].[K+].OO>CS(C)=O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:19])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reaction time: 3 h
Yield: 171.3 %

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinonitrile (3.02 g, 13.5 mmol), powdered K2CO3 (0.93 g, 6.7 mmol), and DMSO (100 mL) in a RB flask and add H2O2, 30% wt. Aq (4.05 mL, 13.5 mmol) by dropwise addition at 0° C. Stir the reaction mixture for 3 hours allowing it to come to room temperature then quench the reaction slowly at 0° C. with water. Extract the product out of the water layer with ethyl acetate several times and then wash with brine. Dry over Na2SO4 and concentrate under reduced pressure to give 2.78 g (95% yield) of the title compound: 1H NMR (500 MHz, DMSO); 7.2 (1H, d), 7.3-7.4 (2H, m), 7.5 (1H, br s), 7.9-8.0 (2H, m), 8.1 (1H, br s), 8.3 (1H, d), 8.7 (1H, s), 10.0 (1H, s); MS m/z 243 (M+1).
Reaction SMILES: [OH:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](O)=[O:12])[CH:7]=[CH:8][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.CC(=O)OCC>C1COCC1.O>[OH:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][C:2]([CH3:15])([OH:1])[CH3:14])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(O)Cc1cccc(CC(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)Cc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
The compound of step 1 (0.132 g, 0.634 mmol) was dissolved in THF (0.5 ml) and added to a refluxing suspension of lithium aluminium hydride (122 mg, 3.1 mmol) in THF (1 ml). The mixture was stirred for 1 h under reflux and cooled to room temperature. Diethyl ether (6 ml) was added, followed by EA (0.4 ml). Subsequently, water was added slowly until the alumina salts formed a thick slurry from which the supernatant could be decanted easily. The slurry was repeatedly washed with EA, the combined extracts were dried with sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield 49 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([NH:17][CH3:16])=[N:19][CH:20]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(NC)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CNc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N-methyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[CH3:31][N:26]1[CH2:27][CH2:28][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 3 h
Yield: 37.9 %

Procedure:
A solution of 3-(naphthalene-1-sulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (73.4 mg, 0.187 mmol) in CH3CN was treated with 37% aqueous formaldehyde (0.15 mL, 2.0 mmol) and sodium triacetoxyborohydride (92.1 mg, 0.435 mmol), stirred for 3 hours at ambient temperatures and partitioned in chloroform and 1.0 N sodium hydroxide. The phases were separated; the organic phase was washed with brine, treated with methanol to aid in solubility, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.3% ammonium hydroxide/3.0% methanol in chloroform to give 5-(1-methyl-pyrrolidin-3-yloxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a light orange foam, 28.8 mg (37.9% yield). The foam was taken up in methanol and chloroform, treated with isopropanolic HCl and concentrated in vacuo at 84° C. for 14 hours to yield the title product as a light orange foam, 27.2 mg, Mass spectrum (+EI, [M+H]+) m/z 408. 1HNMR (500 MHz, DMSO-d6): δ14.20 (s, 1H), 10.38-10.60 (br, 1H), 8.74 (d, 1H, J=8.66 Hz), 8.54-8.56 (m, 1H), 8.28 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.28 (d, 1H, J=2.20 Hz), 7.12 (dd, 1H, J=9.15 Hz and 2.32 Hz), 5.22 (s, 1H), 3.31-3.74 (m*, 3H), 2.85 (s, 3H), 2.03-2.12 ppm (m, 1H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50]C)=[O:49])=[CH:44][CH:43]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=[O:2].[OH-].[Li+].Cl>C1COCC1.O>[C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:39][O:40][CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]([OH:50])=[O:49])=[CH:46][CH:47]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=[O:2]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccc(C(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.5 mg (8 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-{[4-(methoxycarbonyl)benzyl]oxy}-3-phenylpropane-2-yl]amino}-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (example 26) were dissolved in 0.25 ml of THF/water (1:1). 0.8 mg (32 μmol) of lithium hydroxide were added and the batch stirred for 3 hours at RT. Then, the reaction composition was acidized with 1 N hydrochloric acid and extracted three times with 5 ml of ethyl acetate each. The organic phases were dried over magnesium sulphate and evaporated in a vacuum. Following lyophilization from dioxane, the yield was 2.3 mg (71% purity, 22% o. th.) of the title compound in the form of a white solid substance.