Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)c1ccccc1
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1

Procedure:
Using the general method of Example 1, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.76 mmol) was reacted with benzoyl chloride (0.25 g, 1.76 mmol) to provide N1-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 203-206° C. 1H NMR (500 MHz, DMSO-d6) δ8.48 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.60 (dd, J=8.0, 1.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.47 (broad s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.32 (q, J=6.0 Hz, 2H), 2.95 (q, J=7.0 Hz, 2H), 1.87 (quintet, J=7.0 Hz, 2H), 1.70 (quintet, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H); MS (EI) m/e 387.2058 (387.2059 calcd for C23H25N5O).
Reaction SMILES: [Br-].[F:2][C:3]([F:9])([F:8])[CH2:4][C:5](=[O:7])[CH3:6].[CH2:10](OCC)C>>[F:2][C:3]([F:9])([F:8])[CH2:4][C:5]([CH3:10])([OH:7])[CH3:6]
Reactant: CC(=O)CC(F)(F)F
Reactant: CCOCC
Agent: [Br-]
Product: CC(C)(O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Methylmaganesium bromide (1.454 mL, 4.36 mmol) was added dropwise via syringe to a solution of 4,4,4-trifluorobutan-2-one (500 mg, 3.97 mmol) in Diethyl ether (25 mL) at 0° C. and stirred at this temp for 1 hr before warming up to RT. The reaction was quenched with sat. ammonium chloride and extracted with ether. The organic layer was washed with brine, collected, dried over MgSO4, filtered and partially evaporated to give the crude product 4,4,4-trifluoro-2-methylbutan-2-ol (500 mg, 89% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.34 (q, J=11.5 Hz, 2H), 1.88 (br. s, 1H), 1.37 (d, J=0.8 Hz, 6H).
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21]([CH3:25])=[CH:22]2)=[CH:17][CH:16]=1.[H][H]>C1COCC1>[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH:21]([CH3:25])[CH2:22]2)=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C=C(C)CC2
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(C)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.0254 g (0.043 mmol) (S,S)-ethylene-1,2-bis(η5 -4,5,6,7-tetrahydro-1-indenyl)titanium (S)-1,1'-binaphth-2,2'-diolate was dissolved in THF (5 mL). The vessel was degassed by exposure to vacuum (2×~10 sec), put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. Alter equilibration, a solution of n-butyllithium (0.052 mL, 1.58 M in hexanes, 0.083 mmol. 1.91 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.016 mL, 0.126 mmol, 2.9 equiv) and 0.130 g (0.756 mmol, 18 equiv) 7-methoxy-2-methyl-3,4-dihydronaphthalene were then added. The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The pressure vessel was sealed and moved to a fume hood where it was charged to 2150 psig with hydrogen and placed in an oil bath at 70° C. The reaction mixture was allowed to stir for 44 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether/hexane (1/4) and water and separating the layers. The organic extract was distilled at reduced pressure to yield 0.097 g (0.557 mmol, 73%) of 7-methoxy-2-methyl-1.2,3,4-tetrahydronaphthalene with an ee of 90.4%.
Reaction SMILES: [C:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].Br.[C:16]([O:20][C:21]([CH2:23][N:24]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31][N:30]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29][CH2:28][N:27]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:16]([O:20][C:21](=[O:22])[CH2:23][N:24]1[CH2:35][CH2:34][N:33]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:32][CH2:31][N:30]([CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:29][CH2:28][N:27]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:26][CH2:25]1)([CH3:17])([CH3:18])[CH3:19]
Reactant: C=C(C)C(=O)NCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)NCCCCCC(=O)N1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Yield: 113.8 %

Procedure:
A suspension of 6-(methacryloylamino)caproic acid (2.80 g, 14.0 mmol), 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane hydrobromide (7.75 g, 13.0 mmol), N,N-dimethylaminopyridine (1.83 g, 15.0 mmol) and 5 mg BHT in 60 ml dichloromethane was cooled to −5° C. and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.88 g, 15.0 mmol) was added portionwise under stirring. To complete the reaction, the mixture was stirred for 2 h at −5° C. and over night at room temperature. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.00 g, 6.44 mmol) and N,N-dimethylaminopyridine (0.6 g, 4.9 mmol) each time were then added 3 more times at intervals of 2 h and finally left to be stirred for 6 h. The solution was washed 3 times with in each case 50 ml saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated on the rotary evaporator after the addition of 5 mg BHT and dried under fine vacuum. 10.3 g of a yellowish oil was obtained which was purified twice by chromatography (silica gel 60, 0.015-0.040 mm, acetone). The acetone was again distilled off on the rotary evaporator after the addition of 5 mg BHT and the product dried in fine vacuum. 6.13 g (8.8 mmol, 68% yield) of a yellow, highly viscous oil was obtained (HPLC purity: 95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].[CH3:17][NH:18][CH2:19][CH2:20][CH3:21].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([N:18]([CH3:17])[CH2:19][CH2:20][CH3:21])=[O:10])[CH:6]=1)[CH3:2]
Reactant: CCCNC
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
Mix 5-hydroxymethyl-isophthalic acid monoethyl ester (3.3 g, 14.7 mmol), N-methyl propylamine (1.5 mL, 14.7 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.8 g, 14.7 mmol), and 1-hydroxtbenzotriazole hydrate (2.0 g, 14.7 mmol) in dichloromethane (40 mL) and DMF (4 mL). Stir at room temperature for 3 h. Concentrate and redissolve in ethyl acetate (150 mL). Wash with aqueous sodium bicarbonate solution, aqueous ammonium chloride solution, water, saturated aqueous sodium chloride, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (2.5 g, 61%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([CH3:19])[CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2C([O-])=O)=[CH:4][CH:3]=1.[OH-:22].[K+].[CH2:24]([OH:26])C>O.Cl.C(Cl)(Cl)Cl.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:19])[CH2:8][NH:9][C:10]2[CH:11]=[CH:15][C:16]([C:24]([OH:26])=[O:22])=[CH:17][CH:18]=2)=[CH:20][CH:21]=1
Reactant: CCO
Reactant: CC(CNc1ccccc1C(=O)[O-])Oc1ccc(F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: O
Product: CC(CNc1ccc(C(=O)O)cc1)Oc1ccc(F)cc1

Procedure:
A solution of 2.6 g of ethyl p-[2-(4-fluorophenoxy)propylaminobenzoate in 100 ml of 95% ethanol containing 2.7 g of potassium hydroxide was heated to reflux for 2 hours. The reaction was cooled, diluted with 100 ml of water and neutralized with 37% hydrochloric acid. The solid was collected and dried giving a white solid which was dissolved in 25 ml of chloroform and diluted with 1 ml of hexane giving a solid with a m.p. 171°-172° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]C)=[O:16].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cnn(CCc2ccccc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cnn1CCc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 36.2 %

Procedure:
A mixture of methyl 5-methyl-1-phenethyl-1H-pyrazole-4-carboxylate (177 mg, 0.72 mmol), lithium hydroxide monohydrate (111 mg, 2.62 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuum and separated by HPLC (condition: column AD-H (20 mm*250 mm*5 μm), hexane: ethanol (0.2% DEA)=50:50, flow rate: 13 mL/min) to give 5-methyl-1-phenethyl-1H-pyrazole-4-carboxylic acid (60 mg, 36%). LRMS (M+H+) m/z: calcd. 230.11. found 230.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:5][C:6]=1[CH:7]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)[CH3:8].[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30].[H-].[Na+]>CN(C=O)C>[C:29]([O:33][C:34](=[O:37])[CH2:35][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([O:9][CH:7]([C:6]3[S:5][C:4]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:3][C:2]=3[CH3:1])[CH3:8])[CH:18]=2)[CH:14]=[CH:15]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 1 b], [rac]-6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of sodium hydride in DMF to yield [rac]-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[NH:4][C@@H:5]1[C@@H:9]([NH2:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[F:19][C:20]([F:28])([CH2:26][Cl:27])[CH2:21][CH2:22][C:23](O)=[O:24].C(N(CC)CC)C>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[NH:4][C@@H:5]1[C@@H:9]([NH:10][C:23](=[O:24])[CH2:22][CH2:21][C:20]([F:28])([F:19])[CH2:26][Cl:27])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: COC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N
Reactant: O=C(O)CCC(F)(F)CCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1NC(=O)CCC(F)(F)CCl
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of the product from Step 3 (2.20 g, 8.82 mmol), 4,4-difluoro-5-chloropentanoic acid (1.52 g, 8.82 mmol) and triethylamine (3.57 g, 35.3 mmol) in EtOAc (25 mL) was stirred as propanephosphonic acid cyclic anhydride (5.25 mL of a 50% solution of in EtOAc, 8.82 mmol) was added in one portion. After heating at reflux overnight, the reaction was cooled to room temperature, diluted with EtOAc (300 mL) and washed with saturated sodium carbonate solution. The organic layer was dried over sodium sulfate and concentrated to an oil that was separated by silica gel chromatography (Biotage 25+S (A Dynax Corp.; Charlottesville, Va.) eluting with a dichloromethane/methanol/ammonium hydroxide gradient (100:0:0-95:5:0.25). The desired fractions were concentrated and triturated with di-isopropylether to afford 3.56 g (70%) of the product as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 7.36-7.22 (m, 5H), 6.14-6.00 (br s, 1H), 5.17-5.04 (br s, 1H), 4.17-4.04 (br m, 1H), 4.00-3.86 (br m, 1H), 3.74-3.49 (m, 4H), 3.65 and 3.63 (s, 3H), 3.12-2.94 (m, 2H), 2.49-2.43 (m, 1H), 2.42-2.49 (m, 4H). MS 404.2 (AP+, 100).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.CCOC(C)=O>[CH3:20][S:21]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of tert-butyl 3-hydroxypropylcarbamate (431 mg) at 0° C. in dichloromethane, triethylamine (686 μL) was added, followed by methanesulfonyl chloride (209 μL). The reaction was stirred for 15 minutes, then allowed to warm to room temperature and stir for 1 hour more. Additional triethylamine (686 μL) and methanesulfonyl chloride (209 μL) were added. One hour later the reaction was diluted with EtOAc and washed with saturated NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give the titled compound. ESI+ MS: 259 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].Cl[CH:14]=[C:15]([CH3:17])[CH3:16].O>C1COCC1>[CH3:16][C:15](=[CH2:14])[CH2:17][O:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CC(C)=CCl
Reactant: CCOP(=O)(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)COCP(=O)(OCC)OCC
Reaction time: 1 h

Procedure:
Diethyl hydroxymethylphosphonate (3 g, 17.8 mmol, 1 eq) is dissolved in 50 ml of THF to which sodium hydride (0.43 g, 17.8 mmol, 1 eq) is added. 1-chloro-2-methylpropene (1.62 g, 17.8 mmol, 1 eq) is then added. After one hour under magnetic stirring, at ambient temperature and in a nitrogen atmosphere, hydrolysis is performed with 100 ml of water. Extraction is performed with ether (3×50 ml). The organic phases are collected, washed with 100 ml of a saturated sodium chloride solution and dried on sodium sulphate. After evaporation of the solvent, the residual oil obtained is purified by silica gel chromatography (Eluent=ethyl acetate).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15]1.O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15]1
Reactant: CC(C)(C)OC(=O)c1ccn(CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccn(CCN)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 105.5 %

Procedure:
A mixture of 660 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrrole-3-carboxylate, 194 mg of hydrazine monohydrate, and 19 ml of ethanol was stirred at 70° C. for 12 hours. The reaction solution was left to be cooled and the insoluble material was then separated by filtration. The filtrate was concentrated under reduced pressure to obtain 430 mg of tert-butyl 1-(2-aminoethyl)-1H-pyrrole-3-carboxylate as a yellow oily substance.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:18]1[C:19]([CH3:28])=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:3]([O:5][CH3:6])=[O:4].C(O[C:33]([CH3:36])([CH3:35])[CH3:34])(=O)C.Cl(O)(=O)(=O)=O>CO.C(Cl)Cl>[C:33]([O:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:18]1[C:19]([CH3:28])=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:3]([O:5][CH3:6])=[O:4])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
An ice cold solution of methyl 2-hydroxy-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (425 mg, 1.111 mmol) in tert-butyl acetate (15.000 mL, 111 mmol) was treated with perchloric acid (0.191 mL, 2.223 mmol), and stirred for 5 min. The reaction was then kept in the refrigerator without stirring overnight. The reaction was quenched with sat. NaHCO3 at 0° C., extracted with EtOAc 2×, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane, then 0-20% MeOH/DCM) gave methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (224.7 mg, 0.512 mmol, 46.1% yield) as off white solid. NMR showed 2:1 diastereomer. 1H NMR (400 MHz, CHLOROFORM-d) ppm 9.93 (br. s., 1H), 7.19-7.12 (m, 1.4H), 6.99 (d, J=8.4 Hz, 0.6H), 6.77-6.68 (m, 1H), 5.91-5.77 (m, 1H), 5.36-5.10 (m, 1H), 4.27-4.16 (m, 2H), 3.81-3.74 (m, 3H), 3.74-3.62 (m, 3H), 2.77-2.60 (m, 2H), 2.17-2.06 (m, 2H), 1.95-1.88 (m, 3H), 1.16-1.07 (m, 6H), 1.00-0.94 (m, 3H); LCMS (m/z) ES+=439 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Reaction time: 8 h

Procedure:
5-Bromo-2-chloro-3-pyridinamine (10 g) was dissolved in pyridine (75 ml) and methanesulfonyl chloride (7.5 ml) was added and stirred overnight. Further methanesulfonyl chloride (2.1 ml) was added and the reaction stirred at RT for 5 h. Further methanesulfonyl chloride (2.1 ml) was added and the mixture stirred at RT overnight. The ph was adjusted to ˜6 by the addition of 2M HCl (aq). The mixture was then extracted with DCM (2×150 ml) and the combined organic layers were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was suspended in methanol (200 ml) and 2M NaOH (50 ml) was added. The mixture was stirred for 1 hour and then the solvent removed in vacuo. The residue was dissolved in water (250 ml) and washed with DCM (150 ml). The aqueous layer was then acidified and the resulting precipitate collected by filtration. The solid was air dried overnight to give title compound (13.45 g) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:28][OH:29].C(Cl)Cl.[CH3:33][N:34]([CH:36]=O)C>>[C:28]1([O:29][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][C@H:4]([NH2:5])[C:3]([O:2][CH3:1])=[O:21])=[CH:19][CH:18]=2)[C:19]2[C:14](=[CH:15][CH:33]=[N:34][CH:36]=2)[CH:13]=[CH:4][N:5]=1
Reactant: CO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(Oc2nccc3ccncc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of N-(BOC)-(S)-tyrosine methyl ester (1.71 g, 5.80 (mmol) potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 3 (1.0 g, 6.08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h, and at 40° for 18 h. The DMF was removed in vacuo and the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a new colorless oil. Chromatography (silica; 2.5% MeOH/DCM) afforded reasonably pure N-t-butoxycarbonyl protected title compound (1.75 g, 71%). This material was dissolved in EtOAc (40 ml) and HCl gas was bubbled through the stirred solution for 1 min. then the mixture was stirred for an additional 0.5 h. The volatiles were removed in vacuo affording a yellow solid which was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained oil was chromatographed (silica; 5% MeOH/DCM) to afford the title compound as a near colorless oil (0.83 g, 62%) δH (CDCl3) 9.77 (1H. s), 8.75 (1H, d, J 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25 (1H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 3.80-3.70 (1H, obscured m), 3.72 (3H, s), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) and 0.78 (2H, br s); m/z (ES+, 70V) 324 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:12][C:11]([CH:13]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[N:5][CH:4]=1.Cl.C(N=C=N[CH2:36][CH2:37][CH2:38][N:39](C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N)CC1>CN(C)C=O.C(OCC)(=O)C>[CH:38]1([NH:39][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH:13]([C:11]3[NH:12][C:8]([C:6]4[S:7][C:3]([CH2:2][OH:1])=[CH:4][N:5]=4)=[CH:9][CH:10]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:29][CH:28]=2)[CH2:36][CH2:37]1
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4-[1-{5-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-pyrrol-2-yl}-2-(tetrahydro-2H-pyran-4-yl)ethyl]benzoic acid (270 mg) in N,N-dimethylformamide (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg) and N-methylmorpholine (215 μL), and the mixture was stirred for 1 hr. To the reaction mixture was added cyclopropylamine (50 μL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid. The obtained aqueous layer was neutralized with 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (210 mg, yield 71%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 452 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20]CO)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28].[CH2:29](Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:29])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1
Reactant: ClCCl
Reactant: CNCCOC
Product: COCCN(C)CCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 19.1, 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and N-(Methoxyethyl)methylamine CH2Cl2. were converted to yield {5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-methyl-amine as brown oil, MS: 382 (MH+).