Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:24]([CH:34]([CH2:37]O)[CH2:35][OH:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:24]([C@@H:34]1[CH2:35][O:36][C@@H:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=3)=[N:21][CH:20]=2)[O:23][CH2:37]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cn2)cc1
Reactant: CCCCCCCCCCC(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCC[C@H]1CO[C@H](c2ccc(-c3ccc(OCCCCCCCC)cc3)nc2)OC1
Reaction time: 1 h

Procedure:
A solution of 2.2 g of 6-[4-(octyloxy)phenyl]-3-pyridinecarboxaldehyde (prepared in accordance with Example 2) and 1.4 g of 2-decyl-1,3-propanediol in 40 ml of toluene was treated with 5 drops of 10 percent (v/v) sulfuric acid. The mixture was heated to boiling for 1 hour, moist toluene being distilled off and being replaced by fresh toluene. The reaction mixture was then neutralized with triethylamine and, after cooling, washed three times with water, dried over sodium sulfate and concentrated. Chromatographic purification of the residue on 60 g of silica gel with hexane/ethyl acetate (vol. 9:1) and repeated recrystallization of the trans/cis mixture from ethyl acetate gave 0.56 g of pure 5-(trans-5-decyl-1,3-dioxan-2-yl)-2-[4-(octyloxy)phenyl]pyridine; m.p. (C-S) 69.7° C., transition S-SC 137.5° C., cl.p. (SC -I) 179° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:21][CH:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=[O:23]>O1CCCC1.O>[CH2:14]([O:13][CH2:12][CH:11]([OH:23])[CH:10]([OH:21])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: c1ccc(COCC2OC2COCc2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)C(O)COCc1ccccc1
Temperature: 0 °C

Procedure:
4.2 g of the 1,4-bis(benzyloxy)-2,3-epoxybutane thus obtained was dissolved in a mixture comprising 120 ml of tetrahydrofuran and 30 ml of water. Then 30 ml of an aqueous solution containing 6 ml of 60% perchloric acid was added dropwise thereto under ice-cooling and stirring. After stirring at the same temperature for additional 4 hours, the reaction mixture was poured into ice/water and extracted with ether. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to thereby give 2.7 g of 1,4-bis(benzyloxy)-2,3-butanediol as a colorless liquid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([C:26]3[C:27]([CH3:36])=[N:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:25])=[CH:18][C:17]=2[F:37])(=O)=O)=CC=1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:64].[K+]>CC#N.O>[F:37][C:17]1[CH:18]=[C:19]([CH2:22][NH:23][C:24]([C:26]2[C:27]([CH3:36])=[N:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][N:30]=3)=[O:25])[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][CH2:13][CH2:12][F:64]
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2ccc(CNC(=O)c3cc4cccnc4nc3C)cc2F)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nc2ncccc2cc1C(=O)NCc1ccc(COCCF)c(F)c1
Temperature: 25 °C

Procedure:
A flask with a solution of 19 mg 2-[[2-fluoro-4-[[(2-methyl-1,8-naphthyridine-3-carbonyl)amino]methyl]phenyl]methoxy]ethyl 4-methylbenzenesulfonate (0.036 mmol), 26 mg Kryptofix 222 (4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane) (0.069 mmol) and 4 mg KF (0.069 mmol) in 1.0 ml dry MeCN was added to a preheated oil bath and heated at 90 C for 30 min. The reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and concentrated. Flash chromatography gave 9.6 mg (72%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=[C:5]2[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]=[CH:26][CH:25]=[C:24]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[C:5]2[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COC(=O)c1ccc(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)ccc(C)c4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A resealable tube was charged with methyl 6-hydroxy-4-methyl-1-naphthoate (0.087 g, 0.402 mmol), cesium carbonate (0.393 g, 1.21 mmol), and DMF (2 mL). The system was flushed with argon, the tube was sealed, and the mixture stirred at RT for 15 min. 4-Chloro-6,7-dimethoxyquinoline (0.090 g, 0.40 mmol) was added, and the system was again flushed with argon. The tube was sealed and the mixture stirred at 100° C. for 18 h. Additional cesium carbonate (0.393 g, 1.21 mmol) was added and the system was again flushed with argon. The tube was sealed and the mixture stirred at 100° C. for 16 h. The mixture was partitioned between CH2Cl2 and water. The aqueous phase was separated and extracted with CH2Cl2. The aqueous phase was acidified to pH 5-6 with 6 N HCl (aq). The resulting precipitate was filtered and washed with water. The filter cake was dried under vacuum to afford 6-(6,7-dimethoxyquinolin-4-yloxy)-4-methyl-1-naphthoic acid as a light brown solid. MS (ESI, pos. ion) m/z: 390.1 (M+H). Mass Calc'd for C23H19NO5: 389.
Reaction SMILES: N.C(O)C.[CH2:5]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14]/[C:15](=[CH:17]\[C:18]#[N:19])/[C:16]=3[C:6]1=2.[H][H]>[Co].C(O)C>[CH2:5]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14][C:15](=[CH:17][CH2:18][NH2:19])[C:16]=3[C:6]1=2
Reactant: [H][H]
Reactant: N#C/C=C1\CCc2ccc3c(c21)CCO3
Agent: [Co]
Agent: N
Solvent: CCO
Product: NCC=C1CCc2ccc3c(c21)CCO3

Procedure:
A saturated ammonia/ethanol solution (150 ml) and Raney cobalt (8.4 g) were added to an ethanol (150 ml) solution of (E)-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]-furan-8-ylidene)acetonitrile (2.6 g, 13.2 mmol), and the reaction mixture was stirred at room temperature in a hydrogen atmosphere (5 kgf/cm2) for 3 hours. The Raney cobalt was filtered off and the solvent was distilled off under reduced pressure to give 2-(1,6,7,8-tetrahydro-2H-indeno(5,4-b]furan-8-ylidene)-ethylamine. To this residue was added a saturated hydrogen chloride/ethanol solution (100 ml), followed by 1 hour of heating under reflux. The reaction solution was concentrated and the residue obtained was recrystallized from ethanol to give 2.75 g (yield: 88%) of the target compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]#[C:21][C:22]([C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1C(OC(C)(C)C)=O)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].C(=O)(O)[O-].[Na+]>CCO>[Si:1]([O:18][CH2:19][C:20]1[O:38][N:37]=[C:22]([C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:21]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](OCc1cc([C@@H]2CCCN2)no1)(c1ccccc1)c1ccccc1
Yield: 40.1 %

Procedure:
To an EtOH (10 mL) solution of the compound (492 mg) obtained in Example 3-(1), hydroxylamine hydrochloride (139 mg) was added and the mixture was heated under reflux for 17 hours. To the reaction mixture, saturated aqueous sodium bicarbonate (50 ml) was added and the organic layer extracted with AcOEt was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt→MeOH/CHCl3) to give the titled compound (163 mg, brown oil.)
Reaction SMILES: C[O-].[Na+].NC[C:6]([C:8]1[N:9]=[CH:10][N:11]([C@@H:18]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@@H:19]2[F:26])[C:12]=1[N:13]=[CH:14][N:15](C)[CH3:16])=[O:7]>CO>[F:26][C@H:19]1[C@H:20]([OH:21])[C@@H:22]([CH2:24][OH:25])[O:23][C@H:18]1[N:11]1[C:12]2[N:13]=[CH:14][NH:15][CH2:16][C:6](=[O:7])[C:8]=2[N:9]=[CH:10]1
Reactant: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CNC=Nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F

Procedure:
In step 1, compound (41) is dissolved in methanol and treated with a methanolic solution of sodium methylate at room temperature, whereby the cyclization of the substituents on the imidazole ring of compound (41) occurs. This ring-forming reaction may be conducted in the same manner as in the step 18 of SYNTHETIC PROCESS CHART (A). Thus, 3-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one [Compound (42)] is produced.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]1[CH2:12][S:21][C:19](=[O:22])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCCO2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC[C@@H]1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.1 %

Procedure:
To a solution of 3.90 g (14.41 mmol) of (2S)-oxan-2-ylmethyl 4-methylbenzene-1-sulfonate in DMF (40 mL) are added 3.29 g (28.83 mmol) potassium thioacetate at room temperature. After complete addition, the reaction is stirred at room temperature for 18 h, then heated to 50° C. for further 20 h. The reaction mixture is diluted with ethyl acetate (250 mL) and washed with saturated aqueous NaHCO3 solution (2×100 mL) and water (2×100 mL). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to afford 2.79 g of 1-{[(2S)-oxan-2-ylmethyl]sulfanyl}ethan-1-one. Yield: 93%; ES-MS: m/z 175 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.17-1.36 (2H, m), 1.42-1.59 (2H, m), 1.63-1.72 (1H, m), 1.79-1.88 (1H, m), 2.34 (3H, s), 2.84-2.93 (1H, m), 3.10 (1H, dd, J=13.73, 4.27 Hz), 3.30-3.47 (2H, m), 3.98 (1H, dt, J=11.41, 2.08 Hz).
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]([S:19][CH3:20])=[NH:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH2:32][CH:33]=[CH2:34])[C:29](O)=[O:30])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH2:32][CH:33]=[CH2:34])[C:29]([N:18]=[C:17]([S:19][CH3:20])[NH:16][C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH:14]=[N:13][C:12]([CH3:15])=[N:11]3)=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:30])=[CH:26][CH:27]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(C)n1
Reactant: C=CCC(C(=O)O)c1ccc(F)cc1
Agent: I
Product: C=CCC(C(=O)N=C(Nc1ccc(-n2cnc(C)n2)c(OC)c1)SC)c1ccc(F)cc1
Yield: 64 %

Procedure:
Methyl 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide, (1.928 g, 6.95 mmol, from preparation F) and 2-(4-fluorophenyl)pent-4-enoic acid (1.62 g, 8.34 mmol, from preparation AA) were coupled using a procedure analogous to Step A of Example 1 to afford methyl N′-2-(4-fluorophenyl)pent-4-enoyl-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)carbamimidothioate (1.62 g, 3.57 mmol, 64% yield) as a white solid. LC-MS (M+H)+=454.2.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[CH:29][C:28]4=[CH:31][CH:32]=[C:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[N:40]([S:42]([CH3:45])(=[O:44])=[O:43])[CH3:41])[N:27]4[N:26]=3)=[C:20]([O:46][CH3:47])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[CH:29][C:28]4=[CH:31][CH:32]=[C:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[N:40]([CH3:41])[S:42]([CH3:45])(=[O:44])=[O:43])[N:27]4[N:26]=3)=[C:20]([O:46][CH3:47])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: COc1cc(CN2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CN2CCN(C(=O)CN)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C

Procedure:
Into an 8 dram vial, {2-[4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (78 mg, 0.11 mmol), Methylene chloride (2.00 mL), and Trifluoroacetic Acid (1.00 mL, 13.0 mmol) were added. The reaction was stirred at room temperature over the weekend. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid The solid was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The collected fractions afforded N-[2-(2-{4-[4-(2-Amino-acetyl)-piperazin-1-ylmethyl]-2-methoxy-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid. LCMS (E/I+) 579.09 (M+H). NMR 1H (DMSO-d6)-8.96 (s, 1H), 7.93-7.99 (m, 1H), 7.90 (d, 1H, J=8.05 Hz), 7.72 (s, 1H), 7.63-7.73 (m, 1H), 7.52-7.58 (m, 2H), 7.00 (d, 1H, J=4.66 Hz), 6.93-6.98 (m, 2H), 6.74 (d, 1H, J=7.94 Hz), 3.84 (s, 3H), 3.35-3.46 (m, 8H), 3.05 (s, 3H), 2.88 (s, 3H), 2.32 (bs, 4H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:27](O)=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:54]([NH2:58])([CH3:57])([CH3:56])[CH3:55].CCOCC>CN(C=O)C.CCN(C(C)C)C(C)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:27](=[O:28])[NH:58][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[CH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:7]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A solution of BOC-O-(2,6-dichlorobenzyl)-L-tyrosine (Bachem, 2.00 g, 4.54 mmol) in 20 mL of DMF and iPr2NEt (1.6 mL) was cooled to 0° C. and treated with HBTU (1.72 g, 4.54 mmol). The resulting solution was stirred at 0° C. for 30 minutes and treated with tert-butyl amine (0.48 mL, 4.54 mmol). The resulting solution was stirred overnight. The reaction mixture was poured into ether (100 mL) and washed sequentially with saturated aqueous NaHCO3 solution (20 mL) and brine (4×20 mL). The organic phase was collected and dried (MgSO4) and concentrated. The crude reaction product was purified by chromatography (silica gel, 2:1 heptane/EtOAc). The solid obtained was crystallized from hot heptane, collected by suction filtration and dried to give the title compound as a white solid (1.56 g, 69%), mp=82-86° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:36])[N:27]3[C:30]([O:32][CH:33](Cl)[CH3:34])=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:37]([OH:42])(=[O:41])[CH2:38][CH2:39][CH3:40].C(N(C(C)C)C(C)C)C>C(OCC)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:36])[N:27]3[C:30]([O:32][CH:33]([O:41][C:37](=[O:42])[CH2:38][CH2:39][CH3:40])[CH3:34])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CC(Cl)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Reactant: CCCC(=O)O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)OC(C)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21

Procedure:
1-chloroethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2.0 g, 3.60 mmol) was stirred with butyric acid (1.0 mL, 10.81 mmol) and ethyldiisopropylamine (0.94 mL, 5.41 mmol) at 50° C. for 48 hours. The reaction was diluted with diethyl ether (20 mL) and quenched with aqueous saturated NaHCO3 (40 mL). The reaction was extracted with ethyl acetate (2×50 mL) and the combined organics were washed with water (50 mL), brine (50 mL) then dried (MgSO4). The crude product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give 1-(butyryloxy)ethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-90 (628 mg, 23% over 2 steps).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([Cl:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].Cl>>[ClH:34].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(C(C)(C)C)cc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(8.7 mg, 24%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-t-butylphenylsulfonyl chloride (24.9 mg, 0.11 mmol). HRMS-FAB+ for C25H27N2O2SF3.HCl, calculated MH+ (--HCl): 477.18237; found: 477.18134.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:21]([O:23]C)=O)=[N:4][C:5]([CH2:9][C:10]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[OH:8].CO.[NH3:27]>>[OH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][CH2:12][CH2:13][CH2:14]2)=[N:4][C:3]=1[C:21]([NH2:27])=[O:23]
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Yield: 49 %

Procedure:
A solution of methyl 5,6-dihydroxy-2-((1-phenylcyclopentyl)methyl)pyrimidine-4-carboxylate (0.020 g, 60.9 μmol) in ammonia in MeOH (435 μl, 3.05 mmol) was heated at 100° C. for 20 min. The cooled solution was evaporated to dryness. The residue was diluted with MeOH and heated in the presence of Amberlyst resin (H+) until in solution. The material was filtered to remove the resin and evaporated to dryness. Trituration with MeOH followed by washing with Et2O provided the desired product as a white solid (0.011 g; 49%). LCMS: m/z=314 (MH+).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([O:22]CC)=[CH2:21])[CH:14]=[CH:13]2>C1COCC1.O>[Br:8][CH2:22][C:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[N:16]=1)=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ccc2cc(Br)ccc2n1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
NBS (407 mg, 2.287 mmol) was added to a solution of 6-bromo-2-(1-ethoxyvinyl)quinoline (530 mg, 1.91 mmol) in THF (10 mL) and water (2.5 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was partitioned between EtOAc and brine and the organic layer was concentrated. The crude material was purified by flash silica gel chromatography (eluted with Et2O/hexanes, gradient from 0 to 5% Et2O) to yield 2-bromo-1-(6-bromoquinolin-2-yl)ethanone (380 mg) as white solid. LC-MS retention time 3.988 min; m/z 329.84 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])[CH3:3].[Cl:20][C:21]1[C:25]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[S:23][C:22]=1[NH2:33].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:20][C:21]1[C:25]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[S:23][C:22]=1[NH:33][C:11](=[O:13])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: Cn1nccc1-c1c(Cl)sc(N)c1Cl
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1c(Cl)sc(NC(=O)C(CNC(=O)OC(C)(C)C)c2ccccc2)c1Cl
Reaction time: 12 h
Yield: 38.1 %

Procedure:
To a solution of 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-phenylpropanoic acid (342 mg, 1.290 mmol), [3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amine (320 mg, 1.290 mmol) and DIPEA (1.126 ml, 6.45 mmol) in dichloromethane (12.100 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (723 mg, 1.548 mmol) in one portion. After 12 h, additional DIPEA (1.126 ml, 6.45 mmol), 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-phenylpropanoic acid (342 mg, 1.290 mmol) and Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (723 mg, 1.548 mmol) were added and the solution stirred 24 h. The reaction mixture was then dry loaded onto silica and purified by chromatography (0-70% EtOAc in hexanes) affording 1,1-dimethylethyl (3-{[3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-phenylpropyl)carbamate (320 mg, 0.491 mmol, 38.1% yield) as an yellow oil: LCMS (ES) m/e 495, 497 (M, M+2)+.