Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:14]1[C:15]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[N:16][C:17]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:18][C:19]=1[O:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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.[Cu](I)I>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[S:1][C:2]([C:14]3[C:15]([NH:28][C@@H:29]4[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)=[N:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[N:18][C:19]=3[O:20][CH3:21])=[N:3][C:4]=2[CH:9]=1)(=[O:11])[NH2:12]
Reactant: NC(=O)c1ccc2scnc2c1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(C(N)=O)ccc2s1

Procedure:
Following the same procedure as in step 3 of Example 337 using 1,3-benzothiazole-5-carboxamide (60.6 mg, 0.34 mmol, 1.80 equiv), tert-butyl (3R)-3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (100.0 mg, 0.19 mmol, 1.00 equiv), cesium carbonate (0.38 g, 6.00 equiv), Pd(PPh3)4 (39.3 mg, 0.034 mmol, 0.18 equiv) and copper iodide (6.5 mg, 0.034 mmol, 0.18 equiv) in DMF (5.0 mL). The crude product was purified by flash chromatography on a silica gel column eluting with ethyl acetate/petroleum ether (1:15-1:1) to provide the title compound as a white solid. MS m/z [M+H]+ (ESI): 570.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([C:22](OC)=[O:23])[N:21]=3)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:18][CH:19]=[C:20]([CH2:22][OH:23])[N:21]=3)=[CH:15][CH:16]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1coc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1coc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of methyl {2-{4-[(1H-benzimidazol-1-yl)methyl]phenyl}-1,3-oxazol-4-yl}carboxylate (0.1 g, 3 mmol) in THF was added dropwise at −10° C. to a suspension of LiAlH4 (0.011 g, 3 mmol) in dry THF. The reaction mixture was stirred for one hour at −10° C. and quenched with water and 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness to give the title product in 76% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, CDCl3): 8.00 (s, 1H), 7.98 (d, J=8 Hz, 2H), 7.78 (d, J=14 Hz, 1H), 7.67 (s, 1H), 7.55 (s, 1H), 7.2 (m, 5H), 5.4 (s, 2H), 4.59 (s, 2H). LCMS (ESI+) 306 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:15])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11])(=O)=O.S(OC)(OC)(=O)=O>>[OH:15][C:8]1[CH:7]=[CH:6][C:5]([SH:2])=[CH:14][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Solvent: COS(=O)(=O)OC
Product: O=C(O)c1cc(S)ccc1O

Procedure:
6a was prepared from 5a (0.50 g; 2.0 mmol) using the method described in the synthesis of 7c, without alkylation with dimethyl sulfate
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4](=[O:24])[CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9]=1[C:19]([O:21]CC)=[O:20].[OH-].[Li+].O1CCCC1.O>C(OCC)(=O)C>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4](=[O:24])[CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
Mix 3-[(o-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (600 mg, 1.47 mmol), lithium hydroxide (184 mg, 4.4 mmol), tetrahydrofuran (10 mL) and water (10 mL). Stir for 24 hours at room temperature. Dilute with ethyl acetate (40 mL). Acidify while stirring and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue (ethyl acetate/hexane) to yield the title compound as a white powder (480 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20](O)=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:48]1([NH:54][CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:55]1([N:54]([CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[C:20](=[O:21])[CH2:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]=2[CH3:23])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)N(C1CCCCC1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a flask was added 0.180 g (0.5 mmol) of 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, 1.8 mL of anhydrous dichloromethane, 0.194 g (0.6 mmol) of TBTU (o-benzotriazol-1-yl-N,N,N′,N′,-tetramethyluronium tetrafluoroborate), 0.066 mL (0.6 mmol) of dicyclohexylamine and finally 0.22 mL (1.26 mmol) of diisopropylethyl amine. The reaction was stirred at room temperature for 20 hr then diluted with more dichloromethane (10 mL). The solution was washed with dilute aqueous citric acid (2×10 mL), aqueous sodium bicarbonate (10 mL) and water (10 mL) before drying (MgSO4), filtering and evaporating the filtrate. The residue was slurried with a hexanes/ethyl acetate mix to give the title compound. 1H NMR (CDCl3) δ 7.56 (2H, d), 7.40 (2H, d), 7.01 (1H, bs), 6.61 (1H, d), 6.56 (1H, dd), 3.75 (3H, s), 3.63 (2H, s), 3.41 (1H, m), 2.73 (1H, b), 2.38 (3H, s), 0.9-1.8 (20H, m) Mass Spectrum m/e 521/523 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:23]=[C:24]([NH2:35])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1.Cl.N1C=CC=CC=1>C(OCCO)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:21][C:22]1[CH:23]=[C:24]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:19]#[N:20])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
A mixture of 1.0 g (3.53 mmol) of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.93 g (3.88 mmol) of 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamine and 0.41 g (3.52 mmol) of pyridine hydrochloride in 20 mL of 2-ethoxyethanol is heated at 120° C. for 2 hours, then cooled to room temperature. The product mixture is diluted with a saturated solution of sodium carbonate, stirred for 15 minutes and the solid is collected by filtration. The solid is washed with water and dried in vacuo. The crude product is purified by silica gel chromatography, utilizing a 95:5 to 9:1 gradient of methylene chloride/methanol to give 1.13 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>300° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C:7]2=[O:8])[O:3]1.CC(C[AlH]CC(C)C)C>>[CH3:1][C:2]1([CH3:11])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][CH:7]2[OH:8])[O:3]1
Reactant: CC1(C)O[C@@H]2COC(=O)[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Product: CC1(C)O[C@@H]2COC(O)[C@@H]2O1

Procedure:
The synthesis shown in FIG. 1 started with commercially available 2,3-O-isopropylidene-D-erythronolactone (105), which was reduced with DIBAL-H to provide 2,3-O-isopropylidene-D-erythrose (106) according to published methods. Gao et al., J. Amer. Chem. Soc. 1983, 105, 3661-3672. This lactol underwent Wittig olefination with the corresponding methylenetriphenylphosphine ylid to afford the ring-opened alcohol 107 in 60% yield. At this stage, a Swern oxidation protocol was chosen among several methods tested to oxidize 107 to the corresponding aldehyde 108. The resulting aldehyde was found to be unstable and therefore it was utilized immediately for the next reaction. Oxidation of the aldehyde to the acid 109 with sodium chlorite, followed by Dieckmann condensation of the activated acid with ethyl 2-lithioacetate, afforded the desired β-ketoester 110 (59%) plus an unwanted epimerized derivative 111 (9%) as a mixture of separable diastereoisomers. This epimerization problem was surmounted by treating aldehyde 4a directly with ethyl diazoacetate in the presence of tin (II) chloride to provide the keto ester 110 as the sole product in 36% overall yield from alcohol 107. Using a standard protocol, the unsaturated keto ester 110 was converted to the diazo compound 112, which underwent a thermally-induced intramolecular cyclopropanation to give the bicyclo[3.1.0]hexan-2-one derivatives 113 and 114 in a combined 48% yield with a favorable diastereoisomeric ratio (3:1) for the desired isomer 113. The bicyclo derivative 113 was isolated chromatographically and reduced stereospecifically with NaBH4 to give alcohol 115 as a single product in 72% yield. The structure of 115 was confirmed by X-ray analysis, which unambiguously validated the suitability of our synthetic approach to construct (N)-methanocarba carbocyclic nucleosides.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([N:9]=[C:10]=[O:11])[CH2:6][CH2:7][CH3:8]>ClCCl>[CH2:1]([NH:4][C:10]([NH:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCCCN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)NCCC
Reaction time: 8 h
Yield: 92.5 %

Procedure:
205.8 Grams (3.48 moles) of n-propylamine and 250 ml of dichloromethane were charged to a round bottom flask equipped with stirrer, thermometer, reflux condenser and dropping funnel. 313.7 Grams (3.16 moles) of butyl isocyanate were added to the dropping funnel and then metered into the flask with stirring and strong external cooling (solid CO2 bath) at a rate slow enough to maintain the contents generally below 0° C. except for brief excursions to higher temperatures. The resulting mixture was left to stand overnight and then freed of solvent and lights under vacuum with a rotary evaporator leaving 462.3 g of crude product (92.6% crude yield). After further drying of a portion under vacuum a 97.6 area % purity was recorded by gas chromatography. The product contained substantially only one compound by gas chromatography. It melted at 70°-72° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccccc2)c1C(=O)OC
Yield: 83 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), aniline (0.31 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and then filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.60 g of the product at 4:1 hexanes-ethyl acetate, in 83% yield: 1H NMR (CDCl3) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.03-7.16 (m, 4H), 7.29-7.40 (m, 4H), 8.06 (br, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:9])[C:7]2=[CH:30][CH:31]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:9])[C:7]2=[CH:30][CH:31]=1
Reactant: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccc(N)cc3C2=O)ccc1OC
Yield: 92 %

Procedure:
To a solution of methyl 3-(4-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-propionate (2.3 g, 5.4 mmol) in 25 mL of ethyl acetate was added 0.25 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a yellow solid. The crude product was purified by flash column chromatography (silica gel, 20% ethyl acetate/methylene chloride). The resulting solid was dried in vacuo (60° C., <1 mm) to afford 1.98 g (93%) of methyl 3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as a yellow solid: mp 65-67° C.; 1H NMR (CDCl3) δ7.56-7.48 (m, 1H); 7.15-6.93 (m, 3H), 6.85-6.71 (m, 2H), 5.70 (dd, J=6.1, 9.7 Hz, 1H), 4.35 (br s, 2H), 4.09 (q, J=7 Hz, 2H), 3.83 (s, 3H), 3.72 (dd, J=9.7, 16.4 Hz, 1H), 3.62 (s, 3H), 3.23 (dd, J=6.1, 16.4 Hz, 1H), 1.44 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ171.2, 168.3, 168.2, 152.3, 148.9, 148.1, 134.6, 131.4, 125.1, 120.3, 120.2, 117.9, 112.6, 111.2, 108.4, 64.3, 55.9, 51.8, 50.4, 38.1, 14.7; HPLC (Waters Radial-Pak Phenyl column, 1.8×100 mm, 1 mL/min, 240 nm, 55/45, acetonitrile/0.1% aqueous phosphoric acid) 3.5 min, 100%; Anal. Calcd. for C21H22N2O6, 0.29 H2O. Theoretical: C, 62.49, H, 5.63, N, 6.94. Found: C, 62.53; H, 5.62; N, 6.78.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([CH2:32][CH3:33])[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22](=[O:23])[N:21]([C@H:19]2[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:20]2)[CH2:32][CH3:33])=[CH:26][CH:27]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of [(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester the title compound was prepared from 4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester through cleavage of the protecting group with TFA. The title compound was obtained as yellow foam. MS m/e: 474.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1.Br[C:14]1[CH:15]=[C:16]([CH2:21][OH:22])[S:17](=[O:20])(=[O:19])[CH:18]=1>O1CCCC1.O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH:14]2[CH2:18][S:17](=[O:20])(=[O:19])[CH:16]([CH2:21][OH:22])[CH2:15]2)=[CH:7][CH:6]=1
Reactant: O=S1(=O)C=C(Br)C=C1CO
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CSC2CC(CO)S(=O)(=O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. slurry, under argon, of 0.502 g of sodium hydride (60% oil dispersion) in 9 ml of dry tetrahydrofuran is added, dropwise over 5 minutes, 1.69 mi of p-methoxy-α-toluenethiol in 9 ml of dry tetrahydrofuran. The reaction is warmed to room temperature for 30 minutes, recooled to 0° C. and a solution of 2.31 g of product from Example 176 in 10 ml of dry tetrahydrofuran is added. The reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is diluted with 100 ml of water and extracted with diethyl ether. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give an oil. The oil is purified by chromatography (silica gel: 0-90% ethyl acetate/hexane) to give 3.0 g of the desired product (1:1 mixture of isomers).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(Cl)nc2ccccc12
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Product: CCOc1cc(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc12
Yield: 94.5 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (9.93 g) and 2-chloro-4-ethoxyquinoline (4.15 g) were fused at 160° C. for 41/4 hours. The reaction mixture was cooled, dissolved in dilute hydrochloric acid to pH 6 and washed with diethyl ether (2×). The solution was taken to pH 5 and extracted continuously into chloroform. The chloroform extract was evaporated under reduced pressure, dissolved in water, taken to pH 9 with aqueous sodium hydroxide and extracted into diethyl ether (7×) and chloroform (2×). The ether and chloroform extracts were dried (MgSO4) and evaporated to give the title compound as an oil (7.92 g). This was treated with maleic acid in ethanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-ethoxyquinoline dimaleate (8.24 g), m.p. 145.5°-147.5° C. (recrystallised from ethanol).
Reaction SMILES: [ClH:1].C([NH:5][C@H:6]([CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([NH2:19])=[NH:18])[CH2:12][CH2:11]1)[C:7]([OH:9])=[O:8])(=O)C>Cl>[ClH:1].[ClH:1].[NH2:5][C@H:6]([CH:10]1[CH2:11][CH2:12][CH:13]([NH:16][C:17]([NH2:19])=[NH:18])[CH2:14][CH2:15]1)[C:7]([OH:9])=[O:8]
Reactant: CC(=O)N[C@@H](C(=O)O)C1CCC(NC(=N)N)CC1
Agent: Cl
Product: N=C(N)NC1CCC([C@@H](N)C(=O)O)CC1

Procedure:
5 g of (1',4' cis or trans) 2-(R)-acetamido-2-(4'-guanidinocyclohexyl)-acetic acid hydrochloride dissolved in 50.5 ml of 2N hydrochloric acid are refluxed for 2 hours. The mixture is concentrated and cooled. The obtained precipitate is filtered, yielding 4.6 g of a product.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:17]([F:28])[CH:16]=3)=[CH:11][C:10]=2[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:35]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[C:17]([F:28])[CH:16]=3)=[CH:11][C:10]=2[CH2:31][CH:32]([CH3:33])[CH3:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(OC(c3ccccc3)c3ccccc3)c(CC(C)C)c2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1cc(CNc2ccc(CCC(=O)O)c(F)c2)ccc1OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
To a solution of ethyl 3-(4-{[4-(diphenylmethoxy)-3-isobutylbenzyl]amino}-2-fluorophenyl)propanoate (0.50 g, 0.93 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added an aqueous solution (4 mL) of 85% potassium hydroxide (0.20 g, 3.03 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diethyl ether to give the title compound (354 mg, yield 75%) as colorless prism crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[O:9])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:3]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](O)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](O)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclopentyl)-amide (49 mg, 0.093 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.3 ml, 3.8 mmol) was added. The orange reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.5 ml) and ethylenediamine (0.4 ml, 5.7 mmol) was added. The light yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting precipitate was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 29 mg (75%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclopentyl)-amide as an off-white powder. MS: (M+H)+=395; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.42 (br. s., 1H), 9.11 (s, 1H), 8.59 (dd, J=9.1, 5.3 Hz, 1H), 8.42 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.68 (dd, J=9.6, 2.1 Hz, 1H), 7.24 (td, J=9.2, 2.1 Hz, 1H), 4.78 (br. s., 1H), 4.36-4.52 (m, 1H), 4.22 (br. s., 1H), 4.15 (s, 3H), 2.30 (ddd, J=13.7, 8.2, 5.7 Hz, 1H), 2.04-2.19 (m, 1H), 1.67-1.86 (m, 3H), 1.49-1.63 (m, 1H).