Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([Br:16])=[C:11]([O:17][CH2:18][C:19]#[N:20])[CH:10]=[CH:9]3)=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:13]2[C:8](=[CH:7][C:6]([C:5]3[S:1][C:2]4[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=4[C:4]=3[C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[O:17][CH2:18][C:19]#[N:20]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#CCOc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#CCOc1ccc2cc(-c3sc4ccccc4c3C(=O)Cc3ccccc3)ccc2c1Br
Temperature: 25 °C
Yield: 8.4 %

Procedure:
To a 0° C. mixture of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetonitrile (4.87 g, 12.4 mmol) in chloroform (250 mL) was added phenylacetyl chloride (2.0 mL, 15 mmol) and tin (IV) chloride (2.2 mL, 19 mmol). It was refluxed for five hours. During reflux, additional phenylacetyl chloride (2.0 mL, 15 mmol) and tin (IV) chloride (2.2 mL, 19 mmol) were added. The reaction mixture was then allowed to cool to ambient temperature and poured into ice water. It was diluted with additional chloroform and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtrered and solvent evaporated. After stirring the residue in ether and filtering, the filtrate was concentrated and purified by flash chromatography using 25–45% methylene chloride in hexane and 100% methylene chloride as eluent and then further purified by HPLC using 86% acetonitrile (0.1% formic acid) as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for one hour yielded the title compound as a hard amber gum (0.531 g, 8.36%); mass spectrum (+EI, [M+H]+) m/z 512/514. 1H NMR (500 MHz, DMSO-d6): δ8.30 (d, 1H, J=8.70 Hz), 7.74 (d, 1H, J=9.17 Hz), 7.85 (dd, 1H, J=8.70 Hz and 1.83 Hz), 8.21–8.25 (m,2H), 8.07–8.10 (m, 1H), 7.90–7.94 (m, 1H), 7.44–7.50 (m, 2H), 7.13–7.19 (m, 3H), 6.91–6.94 (m, 2H), 5.47 (s, 2H), 3.8 ppm (s, 2H). Elemental Analysis for C28H18BrO2S: Calcd: C, 65.63; H, 3.54; N, 2.73; Found: C, 65.48; H, 3.43; N, 2.35.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13](Cl)(=[O:15])=[O:14])=[CH:5][CH:4]=1.[CH2:17]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23]1)[CH3:18].C(N(CC)CC)C>ClCCl.O>[CH2:17]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([S:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:15])=[O:14])[CH2:23]1)[CH3:18]
Reactant: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: CCOC(=O)CC1CNc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC1CN(S(=O)(=O)c2ccc(OC)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
4-Methoxynaphthylsulfonyl chloride (1.25 g, 5 mmol.) was added portionwise to ethyl-2,3-dihydro-1H indole-3-acetate (1 g, 5 mmol) in dichloromethane (20 cm3), containing triethylamine (1 cm3, 7 mmol) at 0° C. After stirring at room temperature for 4 h, the reaction was diluted with water and the organic layer was separated, dried and concentrated to give ethyl-1-(4-methoxynaphthylsulfonyl)-2,3-dihydroindole-3-acetate as an oil (2 g, 4.7 mmol, 94%). This was then taken up in ethyl alcohol (20 cm3) and aqueous sodium hydroxide (4N, 7 cm3, 28 mmol) was added and the resulting mixture was stirred and heated together at reflux for 2 h. The reaction mixture was then cooled and the ethyl alcohol was removed under reduced pressure. The residue was taken up in water and extracted once with diethyl ether to remove any unreacted ester. The aqueous mixture was then acidified and the product extracted into ethyl acetate. The organic layer was separated, dried and concentrated to provide 1-(4-methoxynaphthylsulfonyl)-2,3-dihydro-indole-3-acetic acid as a solid (1.17 g, 3.00 mmol, 64%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11](O)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.S(Cl)([Cl:23])=O.CN(C=O)C>C1(C)C=CC=CC=1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([Cl:23])=[N:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:19]=1
Reactant: Oc1nc2ccccc2nc1-c1cc2ccccc2o1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2nc1-c1cc2ccccc2o1
Temperature: 110 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
To a suspension of 3-(benzofuran-2-yl)quinoxalin-2-ol (Example 15b, 268 mg, 1.02 mmol) in Toluene (5.1 mL) was added thionyl chloride (0.30 mL, 4.1 mmol) followed by DMF (238 μl, 3.07 mmol). The yellow reaction mixture was stirred at 110° C. for 2 h, cooled to room temperature, and evaporated under reduced pressure to gave a yellow solid. The solid was suspended in dichloromethane (20 ml) and purified by flash chromatography on silica gel (dichloromethane) to give the title compound, 2-(benzofuran-2-yl)-3-chloroquinoxaline (297 mg, quantitative yield), as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[CH3:20][C:21]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[C:22]([NH2:24])=[O:23]>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:29]3[CH2:28][CH2:27][N:26]([C:21]([CH3:25])([CH3:20])[C:22]([NH2:24])=[O:23])[CH2:31][CH2:30]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.1 g) was reacted with 2-methyl-2-(piperazin-1-yl)propanamide via General Procedure B to give 123 mg of 2-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][C:13](O)=[O:14])#[N:7].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+]>CCOCC.O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][CH2:13][OH:14])#[N:7]
Reactant: N#Cc1cccc(C=CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C=CCO)c1
Reaction time: 6 h

Procedure:
Dimethylformamide (0.1 ml) was added to a stirred suspension of 3-cyano-cinnamic acid (30 g) in dry ether (500 ml) containing oxalyl chloride (15 ml). The mixture was stirred for 6 hours, filtered and evaporated to give the crude acid chloride as a pale solid. A solution of this acid chloride in ether (100 ml) and tetrahydrofuran (100 ml) was added to a stirred suspension of sodium borohydride-doped alumina (20 g sodium borohydride on 200 g alumina) in ether (200 ml). The mixture was stirred for 1 hour and then filtered. The filtrate was evaporated and the residue was chromatographed on silica-gel eluting with 2:1 ether:hexane to give the product as a pale oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]#[C:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13].[CH3:17][CH2:18][O:19][C:20](/[C:22](/Cl)=[N:23]\[OH:24])=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:24][N:23]=[C:22]([C:20]([O:19][CH2:18][CH3:17])=[O:21])[C:11]=1[C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: CSc1ccc(C#CC(=O)C2CC2)c(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc(-c2ccc(SC)cc2Cl)c1C(=O)C1CC1
Yield: 35.5 %

Procedure:
A mixture of 1-[2-chloro-4-(methylsulphenyl)phenyl]-3-cyclopropylprop-1-yn-3-one (1.39g) and ethyl chloro-oximidoacetate (0.84 g) in toluene was stirred and heated at reflux overnight. It was cooled and evaporated to dryness. The residue was purified by chromatography eluted with a mixture of hexane and dichloromethane, followed by ether to give ethyl 5-[2-chloro-4(methylsulphenyl)phenyl]-4-cyclopropylcarbonylisoxazole-3-carboxylate (compound 9, 0.72g) as an orange solid, m.p. 50° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH2:16]([NH:15][C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=1)=[O:32])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(CC(=O)NCc1ccccc1)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)NCc2ccccc2)c2ccccc2)c1
Yield: 47.8 %

Procedure:
The procedure is analogous to that described in Example 1, but 0.25 g of 2-(2-amino-N-phenylacetamido)-N-benzylacetamide and 0.11 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from acetonitrile, 0.17 g of N-benzyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido]acetamide melting at 204° C. is obtained.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>CN(C)C=O>[CH2:7]([O:8][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of phenyl-methanol (20.5 g, 190 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2,5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.[Si:14]([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([C:32]([O:34][CH3:35])=O)[CH:26]=[CH:25]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[CH:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[C:37]1=O)[CH2:43]2>C1COCC1.[Cl-].[Cl-].[Cl-].[Ti+3]>[Si:14]([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([CH2:32][O:34][CH:35]=[C:37]1[CH:38]3[CH2:44][CH:42]4[CH2:41][CH:40]([CH2:45][CH:36]1[CH2:43]4)[CH2:39]3)[CH:26]=[CH:25]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COC(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Ti+3]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(COC=C3C4CC5CC(C4)CC3C5)ccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39 %

Procedure:
A 250 mL three-neck flask was fitted with a reflux condenser. 125 mL addition funnel, CaCl2 drying tube and nitrogen line. The apparatus was dried by means of a hot air gun and nitrogen purging. THF (150 mL) distilled from Na/benzophenone was added and the flask cooled in an ice-water bath. Titanium trichloride (12 g, 78 mmol) was added rapidly (fumes in air!) followed by lithium aluminum hydride (1.425 g, 37.5 mmol) in portions with vigorous stirring. The cooling bath was removed and the black mixture was allowed to warm to room temperature. Triethylamine (6 mL, 43 mmol) was added dropwise to the stirred suspension and reflux begun. After 1 hour at reflux, a solution of methyl 6-tert-butyldimethylsilyloxy-2-naphthoate (2.38 g, 7.5 mmol) and adamantanone (1.15 g, 7.67 mmol) in 50 mL of dry THF was added dropwise to the refluxing mixture over an 18 hour period. Reflux was continued for an additional 6 hours. The cooled reaction mixture was quenched by careful addition of 10 mL of methanol and 10 mL of water. The mixture was diluted with 50 mL of pentance and passed down a column of florisil (4"×1.5"), eluting with pentane, then 1:1 ether/pentane. If any of the black material passes through the column it may be removed by extracting the organic phase with water. The pooled organic solutions were concentrated on a rotary evaporator producing a yellow oil which was chromatographed on silica with 5% (V/V) ethyl acetate/hexane. The product containing fractions when evaporated left 1.8 g of a yellow oil which afforded 1.27 g of 1c as slightly yellow crystals from cold pentane: mp 97.5°-98° C.; 1H NMR delta 0.250 (s, 6H), 1.024 (s, 9H), 1.80-1.99 (m, 13H), 2.697 (s, 1H), 3.321 (s, 3H), 7.05-7.72 (m, 6H); 13C NMR delta -4.34, 18.27, 25.73, 28.39, 30.28, 32.32, 37.25, 39.13, 39.28, 57.76, 114.78, 122.19, 126.32, 127.74, 128,06, 128.86, 129.44, 130.88, 131.56, 134.00, 143.73, 153.70; MS m/e (rel. intensity) 435 (37, M+1), 434 (100), 377 (18), 345 (5), 188 (6 ), 162 (18), 14 (11), 73 (20). IR (KBr) 2940, 2915, 1630, 1600, 1480, 1265, 1250, 1090, 855, 840 cm-1. ##STR28##
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>COCCOC.CCOCC.CCCCCCCCCCCC.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]>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[CH:17][CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CCCCCCCCCCCC
Solvent: COCCOC
Product: COc1ccc(Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
A solution of Pd2(dba)3 [92 mg, 0.1 mmol (4.6 mg, 0.005 mmol, 2 mol % Pd per reaction)], ligand 1 (see FIG. 1) [168 mg, 0.4 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [40 mg, 0.4 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 10 mL DME (anhy). After 10 minutes, 0.5 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) K3PO4 (148 mg, 0.7 mmol), 1-bromo-4-tert-butylbenzene (86 μL, 0.5 mmol), and p-anisidine (74 mg, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard. The reaction mixture was purified by preparatory TLC (EtOAc/hexanes as the eluent) to yield 7 mg of the desired product (which was used for calibration with the internal standard). The GC yield was calculated to be 12%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1c(Cc2ccccn2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)COc1cc2c(=O)c(Cc3ccccn3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
10-bromo-2-hydroxy-5-(2-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (190 mg) obtained in Example 85 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (130 mg) was added. After stirring the mixture at room temperature for 30 minutes, t-butyl bromoacetate (110 mg) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water and extracted with methylene chloride. The methylene chloride layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol) to obtain the title compound (88 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:23])=[CH:4][N:3]=1
Reactant: Clc1ccc(Sc2ccccc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloro-5-(phenylthio) pyridine (2.21 g., .01 moles) in 50 ml. of methylene chloride is treated with a methylene chloride solution of 2.02 g. of 85% m-chloroperbenzoic acid. The solution is stirred at room temperature for 1 hour and washed with 50 ml. of aqueous saturated sodium bicarbonate solution. The organic layer is separated dried and evaporated in vacuo to yield 2-chloro-5-(phenylsulfinyl)pyridine.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[CH2:3]([O:6][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:4]#[CH:5]
Reactant: C#CCO
Reactant: O=C(O)CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: C#CCOCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
Sodium hydride (420 mg, 8.75 mmol) was added to propargyl alcohol (68 mL, 1.17 mol) at 4° C. and stirred for 30 minutes at 25° C. 10-Bromodecanoic acid (2g, 7.96 mmol) was added to this mixture and the reaction was stirred at 98° C. for 48 hrs. The reaction mixture was extracted with water and ethyl acetate at pH 1. After drying the organic phase over sodium sulfate, the solvent was removed at reduced pressure. Product was purified over silica gel chromatography in 7-10% ethyl acetate/hexane/0.3% formic acid and then over a second silica gel column in 1-2.5% ethyl acetate/benzene/0.3% formic acid to yield 10-(2-propynoxy)decanoic acid (245 mg, 14%). mp <30° C.; 1H NMR (300 MHz, CDC13) δ 1.25-1.42 (br, 10H, methylene envelope), 1.54-1.70 (bm, 4H, OCH2CH2, CH2CH2COOH), 2.35 (t, 2H, J=7.4, CH2COOH), 2.43 (t, 1H, J=2.3, HC=C), 3.52 (t, 2H, J=6.8, OCH2), 4.14 (d, 2H, J=2.5, C=CCH2O), 10.42 (br, 1H, COOH); 13C NMR (75.4 MHz, CDC13) δ 24.68, 26.06, 29.04, 29.17, 29.35*, 29.46, 34.09, 57.95, 70.22, 74.09, 79.90, 180.02; m/z 227 (M+H).
Reaction SMILES: [C:1]([O-:4])(O)=[O:2].[Na+].[NH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([NH2:22])=[C:14]([Cl:23])[CH:13]=1)[C:8]([OH:10])=[O:9]>O.C1COCC1>[NH2:22][C:15]1[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]([CH2:11][C@@H:7]([NH:6][C:1]([O:4][C:12]([CH3:17])([CH3:13])[CH3:11])=[O:2])[C:8]([OH:10])=[O:9])=[CH:13][C:14]=1[Cl:23]
Reactant: O=C([O-])O
Reactant: Nc1c(Cl)cc(C[C@@H](N)C(=O)O)cc1C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.71 g (35.0 mmol) of NaHCO3 in 100 mL water was added to a solution of 6.5 g (23.0 mmol) of (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid in 140 mL of THF. 15.28 g (70.0 mmol) of Boc-anhydride was added and the mixture was stirred for 3 h at RT. THF was evaporated off i. vac., the aqueous phase was washed with EtOAc and acidified with 10% citric acid solution. The aqueous phase was exhaustively extracted with EtOAc, the combined org. extracts were dried over Na2SO4 and evaporated down i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH2:16])[CH:8]=2)[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]([C:21]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH:16][C:28]([C:27]3[CH:26]=[CH:25][C:24]([C:21]4([C:19]([O:18][CH3:17])=[O:20])[CH2:22][CH2:23]4)=[CH:32][CH:31]=3)=[O:29])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCOCC2)n2nccc2n1
Reactant: COC(=O)C1(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Product: COC(=O)C1(c2ccc(C(=O)Nc3cc(N4CCOCC4)n4nccc4n3)cc2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 34.2 %

Procedure:
7-Morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 110 mg, 0.50 mmol) and 4-(1-(methoxycarbonyl)cyclopropyl)benzoic acid (110 mg, 0.50 mmol) were mixed in pyridine (3 ml). TBTU (160 mg, 0.50 mmol) was then added and the mixture was heated to 80° C. for 15 hours. After cooling to room temperature, additional TBTU (53 mg, 0.17 mmol) was added before the heating continued for another 6 hours. After cooling to room temperature, the reaction mixture was quenched with water and was then concentrated to dryness in vacuo. The crude product was purified by preparatory HPLC (35-55% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (72 mg, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.00 (s, 1 H), 8.10 (d, J=2.3 Hz, 1 H), 7.99 (d, J=8.3 Hz, 2 H), 7.49 (d, J=8.3 Hz, 2 H), 7.41 (s, 1 H), 6.38 (d, J=2.3 Hz, 1 H), 3.88-3.82 (m, 4 H), 3.78-3.70 (m, 4 H), 3.57 (s, 3 H), 1.56-1.50 (m, 2 H), 1.30-1.24 (m, 2 H); ESI-MS: m/z 422.4 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][N:14]3[C:15](=[O:23])[C:16]([C:19](OC)=[O:20])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[NH3:26]>CO>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][N:14]3[C:15](=[O:23])[C:16]([C:19]([NH2:26])=[O:20])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Reactant: N
Solvent: CO
Product: CC(C)c1csc(CCc2ccn3c(=O)c(C(N)=O)cnc3c2)n1
Reaction time: 8 h

Procedure:
A mixture of methyl 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido-[1,2-a]pyrimidine-3-carboxylate (400 mg), concentrated aqueous ammonia (6 ml) and methanol (9 ml) was stirred overnight. Insoluble solids were collected by filtration to obtain the title compound (117 mg). The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to further obtain the title compound (69 mg).