Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH:37]2[CH2:38][CH:34]([CH2:35][CH:36]2[C:39]([OH:41])=[O:40])[CH2:33]1.C(N(C(C)C)CC)(C)C.[Li+].[OH-].FC(F)(F)C(O)=O>C1COCC1.CO>[F:20][C:14]1[C:15]([NH:31][CH:32]2[CH:37]3[CH2:38][CH:34]([CH2:35][CH:36]3[C:39]([OH:41])=[O:40])[CH2:33]2)=[N:16][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:8][CH:9]=2)=[N:12][CH:13]=1
Reactant: NC1CC2CC(C(=O)O)C1C2
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C1CC2CC(Nc3nc(-c4c[nH]c5ncc(F)cc45)ncc3F)C1C2
Temperature: 80 °C

Procedure:
To a solution of 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.187 g, 0.417 mmol) and 6-aminobicyclo-[2.2.1]heptane-2-carboxylic acid, 72h, (0.080 g, 0.417 mmol) in THF (3 mL) was added diisopropylethylamine (0.291 mL, 1.670 mmol). The reaction mixture was heated at 80° C. overnight. Aqueous LiOH (3 mL of 2M solution, 6.000 mmol) was added and the mixture was heated for another 7 hours. The mixture was diluted with MeOH, neutralized with trifluoroacetic acid, filtered and the resulting filrate was purified by preparatory HPLC chromatography to afford 50 mg of desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[F:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(COc2cccnc2N)c(F)c1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1

Procedure:
A mixture of 2-amino-3-(2-fluoro-4-methoxylbenzyloxy)pyridine (1.00 g, 0.004 mol), 4chlorophenyl isothiocyanate (0.68 g, 0.0048 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield0.86g(51%),m.p.138°-140° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][CH2:12][C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)CN[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)CN[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of 2-((trans)-2-(4-bromophenyl)cyclopropylamino)acetamide (100 mg, 0.37 mmol, 1 equiv), 3-trifluoro methyl benzene boronic acid (84 mg, 0.44 mmol 1.2 equiv), K2CO3 (152 mg, 1.11 mmol, 3 equiv) in CH3CN+H2O (4:1) (2 mL) was degassed for 30 min with Argon gas, then Pd(PPh3)4 (0.1 equiv) was added and the reaction mixture was heated at reflux temp. for 2 h. After completion, the reaction mixture was poured into ice water (10 mL), extracted with EtOAc (2×10 mL). The combined extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by prep HPLC to give 2-((trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)acetamide (100 mg, 80% yield) as a white solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:8]=1[CH:9]=[O:10]>CO>[Cl:3][C:4]1[N:5]=[CH:6][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:8]=1[CH2:9][OH:10]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (0.37 g, 9.78 mmol) was added to a 0° C. solution of 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carbaldehyde (1.70 g, 6.52 mmol) in methanol (26 ml). Gas evolution was observed and the reaction mixture was stirred at RT for 30 mins and evaporated. Sat'd NaHCO3 and CH2Cl2 were added to the residue and the aqueous layer was extracted with CH2Cl2 (4×20 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated to give [4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-5-yl]methanol as a light yellow oil. A solution of this alcohol, imidazole (0.89 g, 13.0 mmol) and TBSCI (1.47 g, 9.78 mmol) in CH2Cl2 (22 mL) was stirred at RT overnight. Sat'd NaHCO3 was added and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic phase was dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-35% EtOAc/hexanes) to give the title compound (2.19 g, 89%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.44 (s, 1H), 5.35 (s, 2H), 4.72 (s, 2H), 3.51 (t, J=8.2 Hz, 2H), 0.90-0.96 (m, 2H), 0.89 (s, 9H), 0.09 (s, 6H), 0.00 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chlorophenol as in Example 18 to afford 0.019 g (9%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C22H19O4Cl 383.1050, found 383.1033 (M+1).
Reaction SMILES: N#CN.C(O)(=O)C.[NH2:8][C:9]1[N:10]=[C:11]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=2)[S:12][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](F)[CH:17]=1)=[O:15].BrCC(C1C=CC=C([C:48]([F:51])([F:50])[F:49])C=1)=O>>[NH2:8][C:9]1[N:10]=[C:11]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:26][CH:25]=2)[S:12][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:48]([F:51])([F:50])[F:49])[CH:17]=1)=[O:15]
Reactant: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)sc1C(=O)c1cccc(F)c1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Agent: N#CN
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)sc1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
This compound was prepared from cyanamide, 1-[2-(isothiocyanato-phenoxy)-ethyl]-pyrrolidine of Example 118 and 2-bromo-1-(3-trifluoromethyl-phenyl)-ethanone of Example 127 following a procedure similar to Example 123. Mass spectrum (ES) MH+=477.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[Cl:12][C:13]1[CH:14]=[C:15]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COc1cc(Cl)cc(B(O)O)c1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)cc(-c2n[nH]c3ncnc(N)c23)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 26.8 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.700 g, 2.68 mmoles) in DMF (10 ml), ethanol (6 ml) and water (6 ml), 3-chloro-5-methoxyphenyl boronic acid (0.600 g, 3.21 mmoles) and sodium carbonate (1.40, 13.40 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine Palladium (0.610 g, 0.528 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.198 g, 27% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.66(s, 1H), 8.21(s, 1H), 7.24(t, J=1.6Hz, 1H), .7.13(d, J=1.2Hz, 1H), 7.11(t, J=2.1Hz, 1H), 3.83(s, 3H).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=O)=O.[C:24]([O-])(=[O:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (3R)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (7.50 g, 21.8 mmol) (obtained as described in Reference Example 52(2)) in dimethylformamide (225 ml) was added potassium acetate (6.41 g, 65.3 mmol), and the mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with 10% aqueous sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford (3S)-3-acetoxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (5.51 g, yield 82%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: CC(C)(CN)CO
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(CO)CNCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 18.5 %

Procedure:
Prepared according to the method described in Example 2 from 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.150 g, Example 1b), 3-amino-2,2-dimethylpropanol (0.093 g) and sodium triacetoxyborohydride (0.134 g) in 1,2-dichloroethane (6 ml). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a white powder (0.035 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[C:11]1[CH:33]=[N:32][C:14]2[N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]3[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=3[C:13]=2[CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1>[N:1]1([C:11]2[CH:33]=[N:32][C:14]3[N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]4[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=4[C:13]=3[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Reactant: c1ccc2c(c1)CCN2
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(N3CCc4ccccc43)cnc21
Temperature: 110 °C
Yield: 54 %

Procedure:
Indoline (67 mg, 0.56 mmol) was added to a solution of 3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (210 mg, 0.52 mmol), tribasic potassium phosphate (164 mg, 0.77 mmol) and dicyclohexyl-(2′,6′-diisopropoxy-biphenyl-2-yl)-phosphane (88 mg, 0.19 mmol) in anhydrous toluene (5.0 mL). The reaction mixture was degassed with nitrogen for 10 minutes, heated at 110° C. for 18 h and then allowed to cool to ambient temperature. The resultant mixture was poured into water (40 mL) and extracted with DCM (2×40 mL). The combined organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-40% ethyl acetate in cyclohexane) and the isolated solid triturated with diethylether/pentane and air dried to afford the title compound as a yellow powder (124 mg, 54%). LCMS (Method B): RT=4.83 min, M+H+=442.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[OH-].[Li+]>CO>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)C(C[C@H]1CCCO1)c1ccc(SC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
A solution of 2-(4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (0.693 g, 2.47 mmol) in methanol (10 mL) was treated with a 0.8M aqueous lithium hydroxide solution (4.01 mL, 4.94 mmol). The reaction mixture was stirred at 25° C. for 16 h and then was concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (0.653 g, 99%) as a light yellow oil that crystallized upon standing: mp 105–107° C.; [α]23589=−14.93° (c=0.75, chloroform); EI-HRMS m/e calcd for C14H18O3S (M+) 266.0976, found 266.0976.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[C:30](=[O:32])=[O:31]>O1CCCC1>[Cl:19][C:20]1[C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: O=C=O
Reactant: Clc1ccc2ccccc2n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2nc1Cl
Temperature: -65 °C
Yield: 62 %

Procedure:
To a solution of 21.3 ml (0.15 mole) of diisopropyl amine in 300 ml of dry tetrahydrofuran under a continuous nitrogen blanket, at -70° C., was added 61.6 ml of 2.7M n-butyllithium in hexane (0.165 mole) while maintaining the temperature at -60° to -70° C. Subsequent to this addition, the temperature was maintained at -65° C. for approximately 20 minutes. A solution of 20 g (0.12 mole) of 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise while maintaining the temperature at -60° to -70° C. After holding the temperature at -65° C. for 20 minutes subsequent to this addition, the entire reaction mixture was poured onto a large excess of dry ice. Most of the solvent was evaporated in a stream of air; the residual solvent was removed by rotary evaporation. The residue was taken up in 300 ml water, made basic with dil aq. sodium hydroxide and washed with 3×50 ml of isopropyl ether. The aqueous layer was filtrate and made acidic (4 to 5 pH) with dilute aqueous hydrochloric acid. The precipitate was collected, washed with water, isopropyl alcohol, and isopropyl ether, and dried, giving 15.4 g (62%) of white crystals, m.p. 190°-210° C. (decomp.). A sample was recrystallized from isopropyl alcohol giving an analytical sample, m.p. 190°-210° C. (decomp.).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[CH2:15](Cl)[C:16]#[CH:17].O>CN(C)C=O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:17][C:16]#[CH:15])[C:8]=2[CH:14]=1
Reactant: C#CCCl
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2ccc(N)cc21
Temperature: 0 °C
Yield: 58.5 %

Procedure:
Sodium hydride (0.08 g) was suspended in dry N,N-dimethylformamide (3 ml), and the suspension was cooled to 0° C. While stirring, 6-amino-2H-1,4-benzoxazin-3(4H)-one (0.5 g) was portionwise added to the suspension at 0°, and the resultant mixture was stirred at the same temperature for 30 minutes. To the mixture, propargyl chloride (0.25 g) was dropwise added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 6-amino-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.36 g). m.p., 260.1° C.
Reaction SMILES: BrC[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:10][C:11]([F:20])([F:21])[O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCOc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of ethyl 4-bromobutanoate (2 g, 10.26 mmol) in acetone (20 mL) was added 3-(trifluoromethoxy)phenol (1.52 g, 8.54 mmol), followed by potassium carbonate (3.5 g, 25.36 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (10:1 to 5:1) to give ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate (2.3 g, 92.1% yield) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@@H:12]1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])C.[OH-].[Li+].Cl>CO.C1COCC1.O>[OH:25][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:18]=[CH:17]/[C@H:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[CH2:10]/[CH:9]=[CH:8]\[CH2:7][O:6][CH2:5][C:4]([OH:26])=[O:3]
Reactant: CCCCCC(O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of {(Z)-4-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (0.22 g, 0.6 mmol) in a mixture of 5 mL of methanol and 5 mL THF at room temperature under a nitrogen atmosphere was added an aqueous solution of lithium hydroxide (0.1 g, 2.4 mmol) in 3 mL of water. The reaction was stirred at 45° C. overnight, cooled to room temperature and treated with aqueous hydrochloric acid (1 M) until acidic. The residue was diluted with water (10 mL) and extracted with ethyl acetate. The organic solution was dried (brine, Na2SO4) and evaporated to yield {(Z)-4-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid; ESMS m/Z M+, 339.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cccnc1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3s2)CC1
Yield: 27 %

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (61 mg) was reacted with 28 mg of pyridin-3-yl-3-boronic acid via General Procedure A to give 18.1 mg of 212. MS (Q1) 469.3 (M)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH3:9].[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:23]2[NH:24][N:25]=[C:21]([NH:20][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([CH2:10][N:8]([CH3:7])[CH3:9])=[CH:19][CH:18]=3)[CH:22]=2)[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: CN(C)Cc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CN(C)C)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
Oxalyl chloride (61 μl, 0.69 mmol, 1.1 eq) was added dropwise to 4-(dimethylaminomethyl)benzoic acid (113 mg, 0.63 mmol, 1 eq) in DCM (2.5 ml) containing 1 drop of DMF. After stirring at ambient temperature for 1.5 h, a solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (196 mg, 0.56 mmol, 0.9 eq) and pyridine (137 μL, 1.69 mmol, 2.70 eq) in DCM (2 ml) was added to the reaction mixture and stirring was continued at ambient temperature for a further 2 h. A solution of TFA (384 μL, 5.16 mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continued at ambient temperature for 18 h. The reaction mixture was concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (65 mg, 25% yield).; 1H NMR (399.902 MHz, DMSO) δ 2.09 (6H, s), 2.81 (4H, s), 3.38 (2H, s), 3.65 (6H, s), 6.26-6.25 (1H, m), 6.35 (2H, d), 6.40 (1H, s), 7.31 (2H, d), 7.87 (2H, d), 10.51 (1H, br.s), 12.07 (1H, br.s). MS: m/z 409 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][NH:13]1)=[S:11].C(N(CC)CC)C.C.[C:26](Cl)(Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[N:12]2[N:13]([CH2:14][O:15][CH2:16][CH2:17]2)[C:26](=[O:27])[S:11]1
Reactant: O=C(Cl)Cl
Reactant: S=C(Nc1ccc(Cl)cc1Cl)N1CCOCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1sc(=Nc2ccc(Cl)cc2Cl)n2n1COCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.8 g (6.2 mmol) N-(2,4-dichlorophenyl)tetrahydro-4H-1,3,4-oxadiazine-4-carbothioamide was dissolved in 30 mL toluene and 1 mL triethylamine in the presence of a small quantity of activated charcoal at 0°-5° C. 3.49 g (6.81 mmol) phosgene as 20% solution in 30 mL toluene was added dropwise over 1.5 h. The reaction mixture was then left to warm up to room temperature and stirred overnight. The activated charcoal was removed by filtration and the solvent evaporated in vacuo. The desired product was isolated after chromatography on silica gel.