Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][C@H:12]3[CH3:16])[S:8][C:4]=2[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][CH2:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][C:5]=2[N:6]=1
Reactant: C[C@@H]1CCCN1CCc1nc2ccc(Br)cc2s1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: C[C@@H]1CCCN1CCc1nc2ccc(-c3cccnc3)cc2s1
Temperature: 65 °C
Yield: 68.7 %

Procedure:
A mixture of 6-bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (0.3 g, 0.9 mmol), 3-pyridinyl boronic acid (0.17 g, 1.4 mmol) and 2-(dicyclohexylphosphino)biphenyl (65 mg, 0.2 mmol) in 15 mL of IPA was purged wth nitrogen. Dichlorobis(triphenylphosphine)palladium 11 (65 mg, 0.1 mmol) was added. Sodium carbonate (0.15 g, 1.35 mmol) was dissolved in 5 g of water, purged with nitrogen, and added to the above mixture. The mixture was heated to 65° C. under nitrogen for 16 hr. After cooling to room temperature 20 mL of methylene chloride was added and the solid was filtered off. The filtrate was concentrated to oil and dissolved in 10 mL of 2N HCl. The acidic aqueous layer was washed with 10 mL methylene chloride, the pH adjusted with 4N NaOH to pH 10, and the product free base was extracted with 20 mL methylene chloride. The methylene chloride layer was concentrated to dryness and purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give the pure 2-[2-(2-Methyl-pyrrolidin-1-yl)-ethyl]-6-pyridin-3-yl-benzothiazole (0.2 g, 67% yield). 1H NMR (CDCl3, 400 MHz) δ 1.14 (d, 3H, J=8 Hz), 1.42-1.51 (m, 1H), 1.71-1.86 (m, 2H), 1.92-2.00 (m, 1H), 2.27 (q, 1H, J=8 Hz), 2.41-2.48 (m, 1H), 2.60-2.67 (m, 1H), 3.22-3.37 (m, 4H), 7.36-7.39 (m, 1H), 7.64 (broad d, 1H, J=8 Hz), 7.90 (broad d, 1H, J=8 Hz), 8.03-8.05 (m, 2H), 8.60 (d, 1H, J=4 Hz), 8.89 (d, 1H, J=1.5 Hz); 13C NMR (CDCl3, 400 MHz) δ 19.3, 22.2, 33.0, 34.0, 52.7, 53.8, 59.9, 119.7, 122.6, 123.3, 125.0, 134.2, 135.9, 136.2, 148.0, 148.1, 152.3, 170.7; (DCl/NH3) m/z 324 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:38]1[CH:43]=[CH:42][C:41]([C:44](=[NH:46])[NH2:45])=[CH:40][C:39]=1[C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:38]2[CH:43]=[CH:42][C:41]([C:44](=[NH:45])[NH2:46])=[CH:40][C:39]=2[C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:14])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)c(C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a mixture of 3.4 g of 4-benzyloxybenzoic acid and 50 ml of dried pyridine, while being cooled in ice, was added 3.7 g of DCC. After having been stirred for 30 minutes, the mixture was admixed with 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate and stirred overnight at room temperature. The reaction mixture was freed from the insolubles by filtration and mixed with ethyl ether. The precipitated insoluble substance was recrystallized from a methanol-ethyl ether mixture to obtain 5.2 g of colorless crystals of 4-amidino-2-benzoylphenyl 4-benzoyloxybenzoate methanesulfonate.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([F:24])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)CCC(=O)O
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
A solution of (R)-ethyl 3-amino-4-(5′-chloro-2′-fluorobiphenyl-4-yl)butanoate hydrochloride (Intermediate 8-5: 293 mg, 0.777 mmol), succinic anhydride (93 mg, 0.932 mmol) and DIPEA (0.204 mL, 1.165 mmol) in dichloromethane (4 mL) is allowed to stir for 1.5 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (294 mg). HPLC retention time=1.03 minutes (condition B); MS (m+1)=436.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.07 Hz, 3 H) 2.46-2.58 (m, 4 H) 2.64-2.68 (m, 2 H) 2.87 (A of ABX, Jab=13.64 Hz, Jax=7.83 Hz, 1 H) 2.99 (B of ABX, Jab=13.64 Hz, Jbx=6.57 Hz, 1 H) 4.11-4.22 (m, 2 H) 4.47-4.56 (m, 1 H) 6.60 (br d, J=8.59 Hz, 1 H) 7.05-7.10 (m, 1 H) 7.23-7.27 (m, 3 H) 7.39-7.41 (m, 1 H) 7:44-7.46 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[CH:27]=[C:26]([NH:28]CC4C=CC(OC)=CC=4)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[CH:27]=[C:26]([NH2:28])[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(OCc5cccc(Cl)c5)c(Cl)c4)ncnc3cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 91 h
Yield: 97.4 %

Procedure:
To a stirred heterogeneous mixture of compound 210 (1.46 g, 2.74 mmol) and dry DCM (27 mL) was added trifluoroacetic acid (2.1 mL, 27.4 mmol), followed by anisole (0.60 mL, 5.48 mmol), and the mixture was stirred further at room temperature for 91 h. It was poured into petroleum ether (300 mL) and stirred at room temperature for ca. 30 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (300 mL). The residue left behind was dissolved in mixed solvents of acetone-water=1:1 (ca. 100 mL) and stirred with 5M NH3 (100 mL) at room temperature for 1 h. The solid was filtered and washed successively with acetone-water=1:4 (5×20 mL), petroleum ether-ethyl acetate=3:1 (5×20 mL), and dried to give N4-(3-chloro-4-(3-chlorobenzyloxy)phenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (219) (1.10 g, 97%), mp 251-254° C. (decomp); 1H NMR δ [(CD3)2SO] 9.70 (s, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 8.04 (br s, 1H), 7.73 (br d, J=8.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.48-7.39 (m, 3H), 7.26 (d, J=9.0 Hz, 1H), 7.12 (br s, 1H), 7.65 (br s, 2H), 5.24 (s, 2H). Anal. Calcd for C20H13Cl2N5O: C, 58.27; H, 3.67; N, 16.99. Found C, 58.33; H, 3.57; N, 17.2.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([NH:16][C:17]([NH:19][NH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[O:22])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([NH:20][NH:19][C:17]([NH:16][C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)=[O:18])=[O:22])=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 75 %

Procedure:
In a 250 ml Parr flask, 0.72 g (1.68 mmoles) of N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)carbonylamino]-urea is dissolved in 30 ml of absolute ethanol in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for two hours. After filtration on celite, the filtrate is concentrated under vacuum. The evaporation residue is suspended in diethyl ether (20 ml), agitated and filtered to produce a pale yellow powder with a yield of 75%. Melting point: 245-246° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[C:37](=[O:38])[N:36]2[CH2:39][C@@H:33]([CH2:34][C@H:35]2[C:40]([O:42][CH3:43])=[O:41])[O:32][C:22]2=[N:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]([OH:31])=[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:44][C@H:14]2[O:13][C:12](=[O:45])[NH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:65][N:66]([CH3:71])[CH2:67][CH2:68][CH2:69]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[C:37](=[O:38])[N:36]2[CH2:39][C@@H:33]([CH2:34][C@H:35]2[C:40]([O:42][CH3:43])=[O:41])[O:32][C:22]2=[N:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]([O:31][CH2:69][CH2:68][CH2:67][N:66]([CH3:71])[CH3:65])=[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:44][C@H:14]2[O:13][C:12](=[O:45])[NH:11]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCCCN(C)C)O2
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A reaction tube was charged with the product of step 5 (200 mg, 0.326 mmol) and triphenylphosphine (855 mg, 3.26 mmol). The tube was sealed and THF (3259 μl) was added via syringe at 0° C. 3-dimethylamino-1-propanol (381 μl, 3.26 mmol) was added followed by slow addition of diisopropyl azodicarboxylate (631 μl, 3.26 mmol). After 5 minutes the cooling bath was removed and the mixture was allowed to reach room temperature and stirred for 10 minutes. The reaction tube was heated at 40° C. for 3 hours. The reaction mixture was concentrated to dryness in rotavap and the residue was purified on a gold cap silica gel (80 g) column (gradient: 0 to 60% solvent B in dichloromethane (solvent B: 20% methanol in ethyl acetate)) to give the title compound (210 mg, 0.300 mmol, 92% yield) as a white powder.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([OH:24])=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][O:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>ClCCl.CN(C=O)C>[CH3:52][O:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH:59][C:22]([C@@H:20]2[CH2:21][C@H:19]2[C:16]2[CH:17]=[CH:18][C:13]([NH:12][CH2:11][C:10]3[CH:25]=[CH:26][CH:27]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)=[CH:14][CH:15]=2)=[O:24])=[CH:56][CH:55]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)[C@@H]2C[C@H]2c2ccc(NCc3cccc(Oc4ccccc4)c3)cc2)cc1
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.14 g, 0.40 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (0.23 g, 0.60 mmol). The mixture was stirred for 15 min followed by addition of 4-methoxybenzylamine (0.96 g, 0.80 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a white ppt which was filtered and dried under high vacuum to give the title compound as a white powder (0.12 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 6H), 7.19-7.07 (m, 5H), 6.99 (t, J=7.9 Hz, 2H), 6.91 (t, J=8.3 Hz, 2H), 6.54 (d, J=8.4 Hz, 2H), 5.78 (s, 1H), 4.42-4.40 (m, 2H); 4.28 (s, 2H), 4.00 (s, 1H), 2.46-2.42 (m, 1H), 2.34 (s, 3H), 1.60-1.55 (m, 1H), 1.48-1.44 (m, 1H), 1.21-1.14 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:14][C:15]1[CH:16]=[C:17]2[C:23]([C:24]3[N:29]=[C:28](S(C)=O)[C:27]([F:33])=[CH:26][N:25]=3)=[CH:22][N:21]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:18]2=[N:19][CH:20]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:33][C:27]1[C:28]([NH:1][CH:2]([C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:29][C:24]([C:23]2[C:17]3[C:18](=[N:19][CH:20]=[C:15]([F:14])[CH:16]=3)[N:21]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:22]=2)=[N:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Reactant: CCOC(=O)CC(N)C(C)(C)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)CC
Temperature: 80 °C

Procedure:
To a suspension of ethyl 3-amino-4,4-dimethylhexanoate, 27a, (0.19 g. 1.00 mmol) and 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 25a, (0.54 g, 1.20 mmol) in THF (14.4 mL) was added N,N-diisopropylethylamine (0.26 mL, 1.50 mmol). The mixture was refluxed at 80° C. overnight. After removing the solvents under reduced pressure, the crude product was purified by silica gel chromatography (0-50% EtOAc/Hexane gradient) to afford 155 mg of the desired product as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.61 (dd, J=9.0, 2.9 Hz, 1H), 8.56 (s, 1H), 8.33 (dd, J=2.7, 1.0 Hz, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.19 (dd, J=10.1, 2.2 Hz, 1H), 4.94 (td, J=10.0, 3.7 Hz, 1H), 3.99 (dt, J=13.7, 6.8 Hz, 2H), 2.40 (s, 3H), 1.42 (dt, J=14.1, 6.9 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H), 1.01-0.94 (m, 8H); 19F NMR (282 MHz, CDCl3) δ −130.39-133.75 (dd, J=9.0, 1.1 Hz, 1F), −158.56 (s, 1F); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.18 minutes (M+H) 572.07.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26]>CC(C)=O>[CH2:1]([O:4][C:5](=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:25](=[O:26])[N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)Cc1ccc(O)c(OC)c1
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOC(=O)Cc1ccc(OCC(=O)N(CC)CC)c(OC)c1
Temperature: 60 °C
Yield: 95 %

Procedure:
3-Methoxy-4-hydroxyphenylacetic acid propyl ester (15-A) was dissolved in acetone. To the solution, 2 equivalents of K2CO3 were added, followed by 1.2 equivalent of 2-chloro-N,N-diethylacetamide. Under vigorous stirring, the suspension was warmed to reflux (60° C.) for ˜15 hours. After cooling to room temperature the reaction mixture was filtered and the remaining solvent removed under reduced pressure, giving a 95% yield of a dark yellow oil. The oily product was purified by silica column chromatography to produce the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(N1CC[C@@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C.C[C@H]1CCCCN1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:18][C@@H:14]2[CH3:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: C[C@H]1CCCCN1
Product: C[C@H]1CCCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2R,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g) with (S)-2-Methyl-piperidine to get 1.50 g (38% yield) of the product as a beige oil.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29]C)=[O:28])=[O:23])[CH:9]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])=[O:23])[CH:9]=1
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 30 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of methyl 3-((2-(6-(3-(trifluoromethyl)benzylamino)pyrimidin-4-yl)-4-chlorophenyl)carbamoyl)benzoate (400 mg, 0.74 mmol, 1.00 equiv) in tetrahydrofuran (30 mL), water (30 mL), and lithium hydroxide hydrate (317 mg, 7.55 mmol, 10.00 equiv). The resulting solution was stirred for 4 h at 30° C. in an oil bath. The solution was adjusted to pH 1 with hydrochloric acid (1 mol/L). The resulting solution was extracted with 20 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The product was obtained as 350 mg (90%) of a white solid.
Reaction SMILES: [OH-].[K+].O.[CH3:4][C@:5]12[CH2:22][CH2:21][C@H:20]3[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH2:17][CH2:16][C:15](=[O:23])[CH:14]=4)[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[C:24]([O:26]C)=[O:25]>CO>[CH3:4][C@:5]12[CH2:22][CH2:21][C@H:20]3[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH2:17][CH2:16][C:15](=[O:23])[CH:14]=4)[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[C:24]([OH:26])=[O:25]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O

Procedure:
To a stirred solution of 10.123 g. of potassium hydroxide in a mixture of 11.3 ml. of water and 180 ml. of methanol, is added 15 g. of the methyl carboxylate ester product of Step C. above, which is rinsed in with 22.5 ml. of additional methanol. The reaction mixture is placed in an oil bath and heated to reflux, where it is maintained overnight under a nitrogen atmosphere. The reaction mixture is then removed from the heat, concentrated briefly under the nitrogen stream, and then poured into a mixture of 750 ml. of ethyl acetate and 750 ml. of ice water containing 75 ml. of 2.5 N hydrochloric acid. The reaction mixture is shaken well and the resulting layers are separated. The aqueous layer is extracted again with 750 ml. of ethyl acetate and the combined ethyl acetate extracts are washed with 400 ml. of a saturated sodium chloride solution. The combined extracts are dried, filtered, and concentrated. The product is recrystallized from ethyl acetate to yield 11.78 g., m.p. 255° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[C:36](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH3:36])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (100 mg, 0.2 mmol), Cesium carbonate (131 mg, 0.4 mmol) in N,N-dimethylformamide (5 mL) was added CH3I (0.025 mL, 0.4 mmol) at −15° C. The mixture was slowly warmed to room temperature and stirred for about 30 min. The reaction mixture was added 30 mL of water. The solid was collected to give 70 mg of 313. Yield=60%. 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.51-7.46 (m, 1H), 7.11-6.97 (m, 4H), 6.46 (d, J=8.8 Hz, 1H), 4.18 (t, J=4.8 Hz, 2H), 3.85 (d, J=13.6 Hz, 2H), 3.08 (t, J=4.8 Hz, 2H), 2.59 (t, J=7.2 Hz, 2H), 2.26-2.19 (m, 4H), 1.14 (d, J=6.8 Hz, 6H). ESI-MS: m/z=509 [M+H+]
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:12][NH2:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:14](=S)=[S:15].C(N(CC)CC)C.Cl>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:11][C:14]([SH:15])=[N:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NNC(=O)c1ccc2[nH]ncc2c1
Reactant: S=C=S
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Sc1nnc(-c2ccc3[nH]ncc3c2)o1
Yield: 96.6 %

Procedure:
A suspension of 1H-indazole-5-carbohydrazide (4.40 g, 25.0 mmol), carbon disulfide (3.76 mL, 62.5 mmol) and triethylamine (4.18 mL, 30.0 mmol) in ethanol (100 mL) was heated under reflux for 7 hr. After cooling, the reaction mixture was poured into water, and acidified with 1M hydrochloric acid. The precipitate was collected by filtration, dried and recrystallized from tetrahydrofuran to give the title compound (5.27 g, yield 97%) as colorless crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[O:9][CH2:10][CH2:11][OH:12])=[CH:2]1.[H-].[Na+].CN(C)C=O.Br[CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1.O.C(OCC)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[O:9][CH2:10][CH2:11][O:12][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:2]1
Reactant: COC(=O)C(C)Br
Reactant: OCCOc1cccc(-c2ccsc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(C)OCCOc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.22 g of 2-[3-(3-thienyl)phenoxy]ethanol was dissolved in 7 ml of tetrahydrofuran, and 48 mg of 60% oily sodium hydride was added. After the mixture was stirred at room temperature for 20 minutes, a dimethylformamide solution (5 ml) of 0.14 ml of methyl α-bromopropionate was added. The mixture was stirred at room temperature for 1.5 hours, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane / ethyl acetate=10 / 1] to give 0.22 g of methyl 2-[2-[3-(3-thienyl)phenoxy] ethoxy]propionate as a colorless oil.