Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[CH2:48]([O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:52])[CH3:49].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CC(=O)OCC>[CH2:48]([O:50][C:51]([N:53]1[CH2:54][CH2:55][N:56]([C:12](=[O:14])[C@@H:2]([NH:1][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3][CH2:4][C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:57][CH2:58]1)=[O:52])[CH3:49]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
Z-(L)Glu(OtBu)—OH (5 g), HOBT hydrate (2.5 g) and EDCI hydrochloride (3.1 g) were dissolved in DCM/THF (1/1, 42 ml). After 15 min stirring, 1-ethoxycarbonylpiperazine (2.6 g) was added and the stirring was continued overnight at RT. 150 ml of EA and 60 ml of a NaHCO3 solution were added to the mixture and the phases were separated. The org. phase was washed with 60 ml of a 1M NaHSO4 solution and 60 ml of a NaCl solution, was dried (Na2SO4) and evaporated off. After HV drying, 7 g of the desired compound were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][CH3:17])[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])C.[OH-].[Na+]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]([CH2:16][CH3:17])[C:6]=1[C:4]([OH:5])=[O:3])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnn(CC)c1C(=O)O
Temperature: 25 °C
Yield: 78.5 %

Procedure:
2-Ethyl-2H-pyrazole-3,4-dicarboxylic acid diethyl ester (280 mg, 1.2 mmol) was suspended in a NaOH solution (0.5 M in water, 2.8 ml) and stirred at RT until HPLC analysis indicated the consumption of the starting material (4 h). HCl (1 N, 1 ml) was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), evaporated, and the title compound (200 mg, 81%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=211.1 [M−H+].
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)([CH3:10])[CH3:9].C(OC(=O)C)(=O)C>>[CH:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH:25]([NH:27][C:3](=[O:4])[CH3:2])[CH3:26])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(N)COc1ccc(Oc2ccc(OC(C)C)cn2)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(C)COc1ccc(Oc2ccc(OC(C)C)cn2)cc1

Procedure:
2-[4-(5-Isopropoxypyridin-2-yloxy)phenoxy]-1-methylethylamine trifluoroacetate (624 mg, 1.5 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 251 mg (49%), M+H+: 345.12.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[C:7]2[C:16]3[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:27]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:49].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:49][C:9]1[C:8]2[N:27]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[C:7]=2[C:16]2[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2cnc3ccc(CCC(=O)N4CCOCC4)cc3c2n1CCCN1CCCC1=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccc(CCC(=O)N4CCOCC4)cc3c2n1CCCN1CCCC1=O
Reaction time: 0.17 h

Procedure:
To a stirring solution of crude 1-{3-[2-(2-methoxyethyl)-8-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one, (0.85 g) in dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid (60% pure, 500 mg, 1.91 mmol). After 18 hours concentrated ammonium hydroxide (50 mL) was added and the reaction was vigorously stirred for 10 minutes. p-Toluenesulfonyl chloride (690 mg, 3.60 mmol) was added in one portion and the mixture was stirred for one hour. The fractions were separated and aqueous fraction was extracted with chloroform (3×50 mL). The combined organic fractions were concentrated under reduced pressure. Purification by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-30% CMA in chloroform) followed by recrystallization from acetonitrile provided 75 mg of 1-{3-[4-amino-2-(2-methoxyethyl)-8-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a pale yellow solid, mp 168-170° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C@H:7]([CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH2:6][CH2:5]2.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>CN(C)C=O>[CH2:23]([O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C@H:7]2[CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])=[CH:3][C:2]=1[Br:1])[CH:22]=[CH2:21]
Reactant: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(O)cc21
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc2c(cc1Br)CC[C@H]2CCNC(=O)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
A solution of (S)-N-[2-(5-bromo-6-hydroxyindan-1-yl)ethyl]propionamide (48.8 g, 156 mmol.) in N,N-dimethylformamide (110 mL) was cooled with ice, to which was gradually added sodium hydride (6.35 g, 172 mmol., content 65%). The mixture was stirred for about 15 minutes. When the bubbling of hydrogen gas ceased, allyl bromide (22.7 g, 188 mmol.) was added, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was poured into ice-water, which was neutralized with dilute hydrochloric acid. The organic matter was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel gel column chromatography (ethyl acetate) to afford the title compound (yield 52.97 g, 96%).
Reaction SMILES: [NH2:1][C:2]1([CH2:20][OH:21])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.C1COCC1.[C:27](#[N:30])[CH:28]=[CH2:29].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[NH2:1][C:2]1([CH2:20][O:21][CH2:29][CH2:28][C:27]#[N:30])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2
Reactant: COc1cc(F)c2c(c1)C(N)(CO)c1cc(Br)ccc1O2
Reactant: C=CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)C(N)(COCCC#N)c1cc(Br)ccc1O2
Reaction time: 1.5 h

Procedure:
A 100-mL RBF was charged with (9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methanol (2.318 g, 6.54 mmol), tetrabutylammonium hydrogen sulfate (0.111 g, 0.327 mmol), THF (32.7 mL), and acrylonitrile (2.154 mL, 32.7 mmol) to give a clear solution. NaOH (8.18 mL of a 2N aq. solution, 16.36 mmol) was added, and the resulting mixture was stirred for 1.5 h. The reaction mixture was diluted with EtOAc (70 mL), washed with water (2×50 mL), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give 3-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)propanenitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=7.97 (d, J=2.4 Hz, 1 H), 7.45 (dd, J=2.5, 8.7 Hz, 1 H), 7.19 (dd, J=1.7, 2.9 Hz, 1 H), 7.09 (d, J=8.6 Hz, 1 H), 6.96-6.89 (m, 1 H), 3.77 (s, 3 H), 3.64 (t, J=6.0 Hz, 1 H), 3.54-3.42 (m, J=2.1 Hz, 3 H), 3.38-3.23 (m, 2 H), 2.85-2.74 (m, 2 H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[K+].[K+].[O:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.Cl>O1CCOCC1.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>[Br:10][C:4]1[S:3][C:2]([C:19]2[CH:20]=[CH:21][O:17][CH:18]=2)=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: OB(O)c1ccoc1
Reactant: O=C(O)c1cc(Br)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Br)sc1-c1ccoc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 2,5-dibromo-3-thiophenecarboxylic acid (750 mg, 1.38 mmol)[prepared according to Goto, Hiromasa; Dai, Xiaoman; Narihiro, Harunori; Akagi, Kazuo Macromolecules 2004 37, 7, 2353-2362.] in dioxane/H2O (5:1, 6 mL) was added K2CO3 (486 mg, 3.52 mmol), tetrakistriphenylphosphine Pd(0) (51 mg, 44 umol), and 3-furanboronic acid (108 mg, 0.968 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 12 h, the solution was poured onto H2O (100 mL) and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly: LC-MS (ES) m/z=273.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[Cl:8][C:9]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([Cl:25])[C:10]=1[C:11]([NH:13][O:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:12]>O1CCCC1>[Cl:8][C:9]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([Cl:25])[C:10]=1[C:11]([NH:13][O:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12]
Reactant: COC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CONC(=O)c1c(Cl)ccc(Cl)c1Cl

Procedure:
To 1.25 g. of potassium carbonate in 15 ml. of water and 35 ml. of tetrahydrofuran was added 2.0 g. of methyl [(2,3,6-trichlorobenzoyl)aminooxy]acetate and the resulting mixture was stirred at 50° C., for 2 days. The solvents were evaporated in vacuo and residue dissolved in dilute aqueous sodium hydroxide, washed with ethyl acetate and the aqueous layer acidified with concentrated hydrochloric acid. The resulting aqueous layer was extracted with two portions of ethylacetate, the combined ethyl acetate layers were dried over MoSO4 and concentrated in vacuo to obtain [2,3,6-trichlorobenzoyl)aminooxy]acetic acid, m.p. 145°-147° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2[N:16]([N:24]=[C:25]([C:27](O)=[O:28])[CH:26]=2)[C:17]=1/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]([CH3:37])([CH3:36])[CH2:33][CH2:34][NH2:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2[N:16]([N:24]=[C:25]([C:27](=[O:28])[NH:35][CH2:34][CH2:33][C:32]([CH3:37])([CH3:36])[CH3:31])[CH:26]=2)[C:17]=1/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1/C=C/CC(C)C
Reactant: CC(C)(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(C(=O)NCCC(C)(C)C)nn2c(/C=C/CC(C)C)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
To a mixture of (S,E)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (30 mg, 0.072 mmol) and 3,3-dimethylbutan-1-amine (14.54 mg, 0.144 mmol) in DMF (1.5 mL) was added DIEA (0.063 mL, 0.359 mmol), HATU (54.6 mg, 0.144 mmol) and DMAP (1.756 mg, 0.014 mmol) and the resulting mixture was stirred at room temp for 16 h. At this point LCMS indicated completion of reaction. Water was then added and the mixture was extracted with ether (25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then treated with 1N NaOH (0.216 mL, 0.216 mmol) in MeOH (1.500 mL) at 60° C. for 5 h. Mixture was then cooled and purified by prep-HPLC to afford (S,E)-2-(tert-butoxy)-2-(2-((3,3-dimethylbutyl)carbamoyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (3.7 mg, 7.44 μmol, 10.35% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.29 (t, J=6.0 Hz, 1H), 7.05 (d, J=14.0 Hz, 1H), 6.88 (s, 1H), 5.38 (s, 1H), 3.36-3.29 (m, 2H), 2.62 (s, 3H), 2.40-2.27 (m, 2H), 1.86 (dt, J=13.2, 6.7 Hz, 1H), 1.52-1.44 (m, 2H), 1.08 (s, 9H), 1.00 (d, J=3.7 Hz, 3H), 1.02 (d, J=3.7 Hz, 3H), 0.95 (s, 19H). LCMS (M+H)=473.4.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][N:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]3[C:44]4[C:43](=[O:45])[CH2:42][C:41]([CH3:47])([CH3:46])[CH2:40][C:39]=4[O:38][C:37]4[CH2:36][C:35]([CH3:49])([CH3:48])[CH2:34][C:33](=[O:50])[C:32]3=4)[CH:24]=2)[N:18]=1)[NH2:16].N12CCCN=C1CCCCC2.[Cl-].[NH4+]>C1COCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]3[NH:16][C:1](=[O:2])[O:13][N:14]=3)[N:18]=2)=[CH:24][C:25]=1[CH:31]1[C:32]2[C:33](=[O:50])[CH2:34][C:35]([CH3:49])([CH3:48])[CH2:36][C:37]=2[O:38][C:39]2[CH2:40][C:41]([CH3:46])([CH3:47])[CH2:42][C:43](=[O:45])[C:44]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2cccc(C(N)=NO)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cccc(-c3noc(=O)[nH]3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 2 h
Yield: 69.6 %

Procedure:
1,1′-Carbonyldiimidazole (173 mg, 1.07 mmol) was added to a solution of the N′-hydroxy-6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboximidamide produced in Example 8-1 (424 mg, 0.82 mmol) in THF (8.5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.160 ml, 1.07 mmol) was added to the resulting solution, and the mixture thus obtained was then stirred for 4.5 hours. Subsequently, an aqueous solution of ammonium chloride was added to the reaction solution, and the mixed solution was then extracted with dichloromethane twice. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel thin-layer chromatography (methanol:dichloromethane=1:10, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (309 mg, yield: 69%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].C(NC(C)C)(C)C.[Li].[CH3:21][O:22][C:23](Cl)=[O:24]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:23]([O:22][CH3:21])=[O:24])[CH2:10][CH2:9][CH:8]([CH2:11][CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CCC1CCC(C(=O)OC)CC1
Reactant: COC(=O)Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC1CCC(C(=O)OC)(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A solution of 4-ethyl-cyclohexanecarboxylic acid methyl ester (10.4 g, 61.2 mmol) in THF (25 mL) was added dropwise to a solution of lithium diisopropylamine (11.2 g, 92 mmol) in THF (90 mL) at −78° C. After stirring for 1 h at the same temperature, a solution of methylchloroformate (8.7 g, 92 mmol) in THF (25 mL) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL). THF was removed in vacuo and the aqueous residue was extracted with EtOAc (200 mL×3). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a colorless liquid (14 g) with diisopropyl-carbamic acid methyl ester present. MH+229.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([C:14]#[N:15])=[CH:12][C:11]2[NH:16][N:17]=[C:18]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:10]=2[C:9]1=[O:30].O.NN.O>C(O)C>[NH2:19][C:18]1[C:10]2[C:9](=[O:30])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:13]([C:14]#[N:15])=[CH:12][C:11]=2[NH:16][N:17]=1
Reactant: N#Cc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c(=O)n1-c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: N#Cc1cc2[nH]nc(N)c2c(=O)n1-c1ccccc1Cl
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75.3 %

Procedure:
To a solution of 5-(2-chlorophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-carbonitrile obtained in Step K (203 mg) in ethanol (1.63 mL) was added hydrazine monohydrate (29.3 mg) at room temperature. The reaction mixture was stirred at 50° C. for 20 min, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/dichloromethane) to give the title compound (105 mg).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:15]([O:17]C)=[O:16])[CH:9]=[CH:8]3)[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]3)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2cc(C3(C)CC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(c2ccc3cc(C(=O)O)ccc3c2)CC1
Temperature: 60 °C
Yield: 78 %

Procedure:
A mixture of Methyl 6-(1-methylcyclopropyl)-2-naphthoate (crude 0.91 g, 2.5 mmol) and 2M sodium hydroxide solution (3.8 ml) in methanol (7.6 ml) was heated at 60° C. for 2 hours. After cooling to room temperature, the mixture was washed with diethyl ether (100 ml). The aqueous layer was acidified to pH<3 with 2M hydrochloric acid solution and the mixture was extracted with dichloromethane-methanol (10:1, 150 ml×3 times). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 0.444 g (78% yield for 2 steps) of the title compound as white solid. 1H NMR (300 MHz, DMSO-d6) ppm 0.77-0.92 (2H, m), 0.95-1.11 (2H, m), 1.49 (3H, s), 7.42 (1H, d, J=8.8 Hz), 7.84 (1H, s), 7.90-7.97 (2H, m), 8.01 (1H, d, J=8.8 Hz), 8.54 (1H, s). MS (ESI): m/z 225 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]([O:15][CH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([O:23][CH2:24][O:25][CH3:26])[CH2:18]1)([CH2:12][CH:13]=[CH2:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])C=C.CCCCCCC.C(OCC)(=O)C>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:26][O:25][CH2:24][O:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([CH2:16][O:15][C:4]2([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:1][CH2:14][CH2:13][CH2:12]2)[CH2:18]1
Reactant: C=CCC(CC=C)(OC[C@H]1CCC[C@@H](OCOC)C1)C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: COCO[C@@H]1CCC[C@H](COC2(C(=O)OC(C)(C)C)CCCC2)C1
Temperature: 40 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
140 mg of tert-butyl 2-allyl-2-(cis-3-methoxymethoxycyclohexylmethoxy)pent-4-enoate are dissolved in 5 ml of dichloromethane, 10 mg of Grubbs catalyst (Cl2(Cy3P)2Ru═CHPh) are added under an Ar atmosphere and the mixture is stirred at 40° C. for 48 h. 10 ml of heptane/ethyl acetate (3/1) are added and the solution is filtered through silica gel. This gives 100 mg of tert-butyl 1-(cis-3-methoxymethoxy-cyclohexylmethoxy)cyclopent-3-enecarboxylate as a brown oil. This is dissolved in 2 ml of MeOH, degassed and saturated with Ar. 30 mg of Pd/C (10%) are then added, and the mixture is degassed again. The solution is saturated with hydrogen and stirred at room temperature overnight. Dilution with 20 ml of ethyl acetate and filtration through Celite give 100 mg of crude tert-butyl 1-(cis-3-methoxymethoxycyclohexylmethoxy)cyclopentane-carboxylate. This is taken up in 2 ml of tetrahydrofuran, 0.5 ml of HCl (conc.) is added and the mixture is stirred at room temperature overnight. The solution is neutralized with saturated NaHCO3 solution and extracted three times with ethyl acetate. The organic phases are dried over MgSO4 and concentrated. Chromatography of the residue on silica gel (heptane/ethyl acetate 10/1->1/1) gives 57 mg of tert-butyl 1-(cis-3-hydroxycyclohexylmethoxy)cyclopentanecarboxylate as a yellow oil. For the next step, this is used in crude form.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25](=[O:49])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](=O)[NH:33][CH2:34][C:35]([C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[O:44][CH:45]([CH3:47])[CH3:46])=O>C1COCC1>[CH3:23][O:24][C:25](=[O:49])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[S:10][C:35]([C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[O:44][CH:45]([CH3:47])[CH3:46])=[CH:34][N:33]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)CCCCCCC(=O)NCC(=O)c1cc(Cl)ccc1OC(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCCCCc1ncc(-c2cc(Cl)ccc2OC(C)C)s1
Yield: 45.7 %

Procedure:
Add Lawesson's reagent (31.03 g, 77 mmol) to a solution of 7-[2-(5-chloro-2-isopropoxyphenyl)-2-oxoethylcarbamoyl]heptanoic acid methyl ester (21.80 g, 55 mmol) in THF (550 mL) at room temperature under nitrogen. Heat the mixture at reflux for 3 hours. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:3), to afford 7-[5-(5-chloro-2-isopropoxyphenyl)thiazol-2-yl]heptanoic acid methyl ester (9.96 g, 46%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(C(=O)NC4CCCC4)cc3c2C1
Yield: 41 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and cyclopentylamine, 4.1 mg (41%) of the title compound were recovered.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([O-:16])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[C:4]1([CH2:3][CH2:2][CH2:10][C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 72 %

Procedure:
The above mentioned ester (13 g) was dissolved in chloroform (200 ml). This solution was added dropwise to the solution obtained by dissolving L-phenylalanine (16.5 g) and Na2CO3 (15.9 g) in water (150 ml) while stirring at room temperature. After that, the mixture was stirred for 7 hours and the insoluble matter thus produced was removed by filtration. The filtrate was acidified to pH 1.0 with 6N HCl. The precipitated crystals were filtered, washed with water, and recrystallized from 90% aqueous methanol to obtain N-(4-phenylbutyroyl)-L-phenylalanine (11.2 g) having melting point: 178° C.