Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.C[C@H]1O[C@H]2O[C@H]3[C@H](O[C@@]2(O)C(=O)C1)[C@@H](NC)[C@@H](O)[C@@H](NC)[C@@H]3O.CC(NC)C1OC(OC2C(O)C(OC3OCC(O)(C)C(NC)C3O)C(N)CC2N)C(N)CC1.[O:81]=[CH:82][C@@H:83]([C@H:85]([C@H:87]([C@@H:89]([CH2:91][OH:92])[OH:90])[OH:88])[OH:86])[OH:84]>OCC(CO)O>[OH:81][CH:82]1[O:90][C@H:89]([CH2:91][OH:92])[C@H:87]([OH:88])[C@H:85]([OH:86])[C@H:83]1[OH:84]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CNC(C)C1CCC(N)C(OC2C(N)CC(N)C(OC3OCC(C)(O)C(NC)C3O)C2O)O1
Agent: CN[C@@H]1[C@H](O)[C@H](NC)[C@H]2O[C@@]3(O)C(=O)C[C@@H](C)O[C@H]3O[C@@H]2[C@H]1O
Solvent: OCC(O)CO
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
Eight co-integrants each from the crosses summarized in Table 2 were streaked for single colonies (from cultures cryo-preserved in 10% glycerol; described in Section 6.4)) on Luria broth plates with ampicillin (100 μg/ml), spectinomycin (50 μg/ml) and gentamycin (10 μg/ml). Single colonies were inoculated into Luria broth liquid (without drug) and incubated overnight at 37° C. with gyratory shaking. Ten microliters (each) from these cultures were spread on a MacConkey Agar (base; Becton Dickson, Difco Division, Franklin Lakes, N.J.) plated with 2% galactose and 100 μg/ml ampicillin. Following overnight growth three types of galactose-resistant colonies appeared on the agar surface: red colonies (with various morphologies), white opaque colonies and white translucent colonies, in numbers varying from a few dozen to several hundred. Resolved co-integrants were among the white translucent colonies, and a single white colony was picked from each spot, and re-streaked for purification on the same MacConkey agar. These purified white colonies were tested for spectinomycin resistance (50 μg/ml) and gentamycin resistance (10 μg/ml). The resultant colony types are summarized below in Table 4 (Gent=gentamycin, Spec=spectinomycin, R=resistance, and S=sensitivity)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)C=Cc1cc(C)cc(OC)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cc(C)cc(OC)c1
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To a solution of ethyl 3-(3-methoxy-5-methylphenyl)acrylate (2.00 g) in methanol (50 mL) was added 10% palladium-activated carbon (300 mg), and the mixture was stirred for 15 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.00 g) as a yellow oil.
Reaction SMILES: C[Si](OC(C1S[C@H]2N(C(=O)[C@H]2N[Si](C)(C)C)C=C1/C=C/CI)=O)(C)C.[CH2:26]([N:36]1[CH2:41]COC[CH2:37]1)[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35]COC[CH2:31]1>>[CH3:31][N:30]([CH3:35])[CH2:29][CH2:28][CH2:27][CH2:26][N:36]([CH3:41])[CH3:37]
Reactant: C(CCN1CCOCC1)CN1CCOCC1
Agent: C[Si](C)(C)N[C@@H]1C(=O)N2C=C(/C=C/CI)C(C(=O)O[Si](C)(C)C)S[C@H]12
Product: CN(C)CCCCN(C)C

Procedure:
By operating in an analogous manner to the procedure described in Examples 56-81(a), (E)-(6R,7R)-3-(3-iodo-propenyl)-8-oxo-7-trimethylsilanylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-4-carboxylic acid trimethylsilanyl ester was reacted with 4,4′-butane-1,4-diyl-bis-morpholine, and with N,N,N′,N′-tetramethyl-1,4-butanediamine, respectively, to give
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:8][C:9]=1[N:10]([C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (55 mg, 0.121 mmol) was dissolved in methanol (1.2 ml), cooled to 0° C. and then sodium borohydride (4.6 mg, 0.121 mmol) was added. After 30 minutes of stirring at 0° C., the reaction was quenched with a 10% solution of hydrochloric acid (5 ml) and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was then purified by preparative chromatography (3% MeOH/CH2Cl2) to obtain 34 mg (62%) of 3-[(trans-4-Hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:47]=[CH:48][CH:49]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:27][C:28]([C:30]2[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=2)[CH2:33][S:34][CH2:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:29])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=3)[CH2:33][S:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:29])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:47]=[CH:48][CH:49]=[C:3]([C:2]([F:51])([F:1])[F:50])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)phenyl)carbamoyl)-benzylthio)propano ate (600 mg, 0.84 mmol, 1.00 equiv) in dichloromethane (20 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2.5 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 96.2 mg (15%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.92 (s, 1H), 9.51 (t, J=11.7 Hz, 1H), 8.95 (d, J=5.4 Hz, 1H), 8.28 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.82 (d, J=5.4 Hz, 2H), 7.73 (t, J=12.3 Hz, 2H), 7.55 (m, 5H), 6.96 (d, J=2.4 Hz, 1H), 6.76 (m, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.87 (s, 2H), 3.33 (s, 4H), 2.62 (m, 2H), 2.50 (m, 2H), 1.99 (s, 4H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=1O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([CH3:37])[C:31]=3[CH3:30])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1cccc(O)c1C
Product: Cc1cccc(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1C

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}methanol and 2,3-dimethylphenol according to the procedure of Example 69. MS (ESI) m/z 498.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc(Br)cc1)S(C)(=O)=O
Reaction time: 24 h
Yield: 83.2 %

Procedure:
Methyl iodide (2.38 g, 0.0382M) was added to a mixture of N-(4-bromophenyl)methanesulfonamide (6.37 g, 0.0255M) and potassium carbonate (5.21 g, 0.0382M) in dimethylformamide (50 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for a further 24 hrs after which time it was partitioned between diethylether (100 ml) and water (100 ml). The aqueous was extracted further with diethyl ether (2×100 ml). The combined organics were dried over magnesium sulfate, filtered and the solvent concentrated in vacuuo to afford the title compound as a white solid (5.6 g). 1H NMR (CDCl3): 2.94 (s, 3H), 3.04 (s, 3H), 6.89 (d, J=2.56 Hz, 2H), 7.30 (d, J=2.56 Hz, 2H),).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:13]([C:14]#[N:15])=[CH:12][S:11][C:10]=1[C:16]([O:18]C)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[K+]>[C:23]([O:22][C:20]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:13]([C:14]#[N:15])=[CH:12][S:11][C:10]=1[C:16]([OH:18])=[O:17])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1scc(C#N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(C#N)csc1C(=O)O
Temperature: 50 °C
Yield: 87.3 %

Procedure:
A mixture of methyl 3-bis(t-butoxycarbonyl)amino-4-cyanothiophene-2-carboxylate (38 g, 99.5 mmol) in methanol (160 ml) and 2N potassium hydroxide (50 ml) was heated at 50° C. for 3 h. The methanol was evaporated and the mixture was acidified (pH=5) with acetic acid. The mixture was extracted with ether, dried and concentrated in vacuo. The residue was triturated with petroleum ether and the crystallinic fraction was filtered off to give 32 g (87%) of 3-bis(t-butoxycarbonyl)amino-4-cyanothiophene-2-carboxylic acid. M.p. 159°-160° C. 1H-NMR (CDCl3, δ): 1.45 (s, 18H), 8.1 (s, 1H), 8.5 (br.s, 1H).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:36])[C@H:15]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:16]1[C:17]([I:30])=[C:18]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=3[S:23][C:19]2=[N:20][C:21]=1[CH3:22])C1C=CC=CC=1.O.[OH-].[Li+].OO.S([O-])([O-])=[O:43].[Na+].[Na+].Cl>O1CCCC1.O>[O:31]([C@H:15]([C:16]1[C:17]([I:30])=[C:18]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=3[S:23][C:19]2=[N:20][C:21]=1[CH3:22])[C:14]([OH:36])=[O:43])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1nc2sc3c(c2c(I)c1[C@@H](OC(C)(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)CCCC3
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2sc3c(c2c(I)c1[C@@H](OC(C)(C)C)C(=O)O)CCCC3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R)-2-tert-butoxy-2-(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetyl]-1,3-oxazolidin-2-one (Preparation 13A, 23.75 g, 38.40 mmol) in tetrahydrofuran (450 mL) and water (150 mL) at 0° C. was added dropwise a solution of lithium hydroxide hydrate (3.35 g, 80.64 mmol) and hydrogen peroxide (27% aqueous, 18.3 mL, 161.27 mmol). The resulting solution was stirred at 0° C. for 15 minutes, then for 2 hours at room temperature. A saturated solution of sodium sulphite (500 mL) was added followed by water (500 mL), and the mixture stirred for 15 minutes. The mixture was acidified to pH 4 by the addition of 6 M hydrochloric acid. The mixture was extracted with dichloromethane (4×500 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting white solid was crystallised from methylated spirits (150 mL) with heating at reflux for 5 minutes. The Mixture was allowed to cool to room temperature overnight. The resulting solid was collected by filtration and washed with cold methylated spirits and dried in vacuo to give the title compound as a white solid, 12.01 g, in a 68% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](O)=[O:18])=[CH:9]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][CH:9]=2)=[O:18])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
3-aminopyridine (290 mg, 3.1 mmol) and indole-3-carboxylic acid (500 mg, 3.1 mmol) was dissolved in DMF (20 ml), DCC (579 mg, 3.1 mmol) was added to the solution, and then the mixture was stirred at 60° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (300 mg, 42%) by chromatography (methanol:dichloromethane=1:20).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH2:28][CH3:29].[CH:30]([O:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1)([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:28]([C:3]1[N:4]=[C:5]([CH2:25][CH2:26][CH3:27])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:7](=[O:8])[C:2]=1[C:37]1[CH:36]=[N:35][C:34]([O:33][CH:30]([CH3:32])[CH3:31])=[CH:39][CH:38]=1)[CH3:29]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: CC(C)Oc1ncccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 70.8 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.49 g) and 2-isopropoxy-3-pyridylboronic acid (0.43 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.04 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.39 g, 70%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CC=CC=1.[CH3:25][NH:26][C:27](=[S:30])[NH:28][NH2:29]>CN(C)C=O>[CH3:25][N:26]1[C:4]([CH2:3][O:2][CH3:1])=[N:29][N:28]=[C:27]1[SH:30]
Reactant: CNC(=S)NN
Reactant: COCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCc1nnc(S)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 192.4 %

Procedure:
5 g of methoxy-acetic acid (55.5 mmol) were dissolved in 70 ml of dimethylformamide. 11.73 g of 1,1′-carbonyldiimidazol (72.3 mmol) were added in portions within 10 min. After 30 min. at room temperature 23 ml of pyridin were added. Then 5.84 g of 4-methyl-3-thiosemicarbazide (55.5 mmol) were added and the obtained solution was stirred at room temperature overnight, and for an additional 3 h at 100° C. The solvent was evaporated, the residue dissolved in 70 ml of saturated aqueous sodium chloride solution and 30 ml of water. The aqueous layer was extracted six times with 100 ml of ethyl acetate each, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated to dryness to yield 17 g of the crude title compound, which was further purified by silica gel chromatography with ethyl acetate, thereby obtaining 7.1 g of the purified title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][CH2:15][CH3:16])[C:8]([CH:17]=[O:18])=[CH:7]2)[CH3:2].[BH4-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][CH2:15][CH3:16])[C:8]([CH2:17][OH:18])=[CH:7]2)[CH3:2]
Reactant: CCNc1nc2ccc(OCC)cc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OCC)cc2cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a stirred solution of 6-ethoxy-2-(ethylamino)quinoline-3-carbaldehyde SLA 41034 (0.605 g, 2.48 mmol) in THF (50 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.094 g, 2.48 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (40 mL). After stirring for 15 min at that temperature, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (6-ethoxy-2-(ethylamino)quinolin-3-yl)methanol SLA 41040 as an orange solid (481 mg, 79% yield).
Reaction SMILES: [CH:1]([C:3]1([OH:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH:15]=[CH2:16])=[CH2:2].FC(F)(F)S([O-])(=O)=O.[Li+]>C(Cl)Cl>[C:3]1(=[O:17])[CH2:1][CH2:2][CH2:16][CH2:15][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14]1
Reactant: C=CC1CCCCCCCCCCC1(O)C=C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: ClCCl
Product: O=C1CCCC=CCCCCCCCCCC1
Reaction time: 0.33 h
Yield: 69 %

Procedure:
A mixture of 1,2-divinylcyclododecan-1-ol (0.125 g, 5.10-4 mol), lithium trifluoromethanesulphonate (0.080 g) and mercuric trifluoroacetate (0.045 g) in methylene chloride (5 cc) is kept at a temperature of the order of 20° C. for 20 minutes. The reaction mixture is washed with a saturated aqueous solution of sodium bicarbonate (3×10 cc) and then extracted with methylene chloride (3×10 cc). The organic extracts are dried over magnesium sulphate. After filtration and concentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa), cyclohexadec-5-en-1-one (0.085 g) is obtained with a yield of 69%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:10]=[C:15]([NH:14][CH:11]([CH3:13])[CH3:12])[NH:9][C:4]=2[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N=C=S
Reactant: Nc1ccc(Cl)c(Cl)c1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)c(Cl)ccc2[nH]1
Yield: 55.5 %

Procedure:
3,4-Dichloro-1,2-phenylenediamine (8.00 g, 45.19 mmol), isopropyl isothiocyanate (5.26 g, 51.99 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (25.0, 59.02 mmol), and pyridine (250 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 6.12 g (55%) of a white solid. MS (EI): m/z 244 (M+H); 1H NMR (DMSO-d6) δ: 11.08 (s, 1H, NH), 7.07 (d, J=8.3Hz, 1H, ArH), 7.00 (brs, 1H, NH), 6.99 (d, J=8.3Hz, 1H, ArH), 3.91 (m, 1H, CH), 1.21 (d, J=6.5 Hz, 6H, overlapping CH3).
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([CH2:17]Br)=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][S:20]([O-:22])=[O:21].[Na+].O>CN(C)C=O>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([CH2:17][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Oc1ccc(CBr)nc1)c1ccccc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(OS(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a solution of 6-(bromomethyl)pyridin-3-yl benzenesulfonate (30 g) in N,N-dimethylformamide (200 mL) was added sodium methylsulfinate (11.2 g), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (30 g, yield 100%) as white crystals.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH2:33][C:34]([F:37])([F:36])[F:35])[N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:36][C:34]([F:35])([F:37])[CH2:33][N:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:38])=[O:3])=[CH:10][CH:11]=2)=[CH:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:30])[F:32])=[CH:24][CH:23]=2)=[N:19]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 1 f], {6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].[F:14][C:15]([F:30])([F:29])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([CH2:25][C:26](O)=[O:27])[N:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C>[F:30][C:15]([F:14])([F:29])[C:16]1[C:24]2[CH2:23][CH2:22][CH:21]=[CH:20][C:19]=2[N:18]([CH2:25][C:26]([NH:1][C:2]2[S:10][C:5]3[CH2:6][O:7][CH2:8][CH2:9][C:4]=3[C:3]=2[C:11]([NH2:13])=[O:12])=[O:27])[N:17]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: NC(=O)c1c(N)sc2c1CCOC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2C=CCC3)sc2c1CCOC2
Temperature: 120 °C
Yield: 9 %

Procedure:
2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide (40 mg, 0.20 mmol) and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-1-yl)acetic acid (50 mg, 0.20 mmol) were dissolved in DCM/DMF (3 mL/50 μL) and polymer supported carbonyldiimidazole (330 mg, 1.2 mmol/g, 0.396 mmol) added. The reaction mixture was heated at 120° C. for 10 min in the microwave. The reaction mixture was filtered washing with MeOH (10 mL), EtOAc (10 mL), and MeCN (10 mL). The filtrate was concentrated in vacuo to give a yellow gum. Purification by preparative reverse phase HPLC gave desired product as a white solid (7.6 mg, 0.018 mmol, 9%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[F:29][C:30]1[CH:48]=[C:47]([CH:49]=O)[CH:46]=[CH:45][C:31]=1[O:32][CH2:33][C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35]>>[NH2:37][C:34]([CH3:36])([CH3:35])[CH2:33][O:32][C:31]1[CH:45]=[CH:46][C:47]([CH2:49][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:48][C:30]=1[F:29]
Reactant: CC(C)(COc1ccc(C=O)cc1F)NC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N)c(F)c2)c1
Yield: 73.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl [2-(2-fluoro-4-formylphenoxy)-1,1-dimethylethyl]carbamate (72 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (19 mg) was obtained.