Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[S:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[OH:1][C:2]1[C:3]([C:8]2[S:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)c1ncccc1O
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ncccc2O)n1
Yield: 32 %

Procedure:
A solution of 3-hydroxythiopicolinamide (500 mg) in dry ethanol (25 ml) was added dropwise to a solution of ethyl bromopyruvate (0.542 ml) in dry ethanol (20 ml) under nitrogen atmosphere and the mixture was refluxed for 2 hours. The solvent was removed from the reaction mixture, and the residue was treated with water, neutralized with 4% aqueous sodium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl, dried (anhydrous Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:benzene=1:9). The second fraction was concentrated. The produced solids were recrystallized from methanol-water to give yellowish crystals of ethyl 2-(3-hydroxy-2-pyridyl)-4-thiazole carboxylate (260 mg, 32%), m.p. 131°-134° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](OCC)=[O:11].CC(C)=O.C(=O)=O.CC(C[AlH]CC(C)C)C>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a 50-mL round-bottom flask, a total of 2.28 g (12 mmol) of ethyl 2-indolecarboxylate was dissolved in 15 mL of dry THF under N2. The solution was cooled to -78° C. (acetone-dry ice bath) and 24 mL (24 mmol) of 1.0M DIBAL in THF was added over a period of 1 h. The mixture was stirred for 2 h at -78° C., quenched with 10 mL of 1N HCl, then allowed to warm to room temperature. The reaction mixture was then extracted with ether (4×100 mL) and the ether layer was washed with 1N HCL (2×100 mL), dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by flash chromatography (1:1 ethyl acetate:petroleum ether). Yield: 1.76 g (99%). 1H NMR (CDCl3): δ1.86 (t, 1H, J=6, OH), 4.82 (d, 2H, J=6), 6.40 (s, 1H), 7.0-7.3 (m, 2H), 7.34 (d, 1H, J=7.8), 7.58 (d, 1H, J=7.8), 8.36 (br s, 1H) MS (EI): m/z 147 (M+).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[OH:21])[C:15]([OH:17])=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15]([OH:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)C1=CC(=Nc2cc(C(=O)O)ccc2O)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2cc(C(=O)O)ccc2O)cc(C(C)(C)C)c1O
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-4-hydroxybenzoic acid, 0.05 g of 5% palladium on charcoal catalyst, 250 ml of ethanol and 50 ml of tetrahydrofuran was placed on a Paar apparatus. Hydrogen uptake was complete in about 10 minutes. The reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give a tan solid which was recrystallized from a mixture of 40 ml of ethanol and 15 ml of water to give 3.2 g of reddish tan granular 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-hydroxybenzoic acid, m.p. 254.5°-255° C. (dec). Analysis: Calculated for C21H27NO4 : %C, 70.6; %H, 7.6; %N, 3.9; Found: %C, 71.0; %H, 7.6; %N, 4.1.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[I:9][C:10]1[C:18]2[C:13](=[CH:14][C:15](/[CH:19]=[C:20]3/[C:21](=[O:29])[NH:22][C:23]4[C:28]/3=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:16][CH:17]=2)[N:12]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:11]=1>CN(C=O)C>[I:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([C@H:19]3[C@@:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][C:21]4=[O:29])[CH2:2]3)=[CH:16][CH:17]=2)[N:12]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[N:11]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trimethylsulfoxonium iodide (1.89 g, 8.6 mmol) in anhydrous DMF (40 mL) was added sodium hydride (60% dispersion in oil) (1.03 g, 25.8 mmol) at 0° C. The mixture was stirred for 15 min after which time (E)-3-((3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (2.2 g, 4.3 mmol) was added. The solution was stirred overnight at rt. The reaction was quenched with sat. NH4Cl solution (50 mL), extracted with EtOAc (4×100 mL), dried over MgSO4 and concentrated to dryness. The title compound was isolated by silica gel chromatography (CH2Cl2/MeOH 98:2) as a yellow solid (1.5 g, 66%). 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.39 (d, 1H J=8.3 Hz), 7.09 (t, 1H, J=7.5 Hz), 7.04 (d, 1H, J=8.0 Hz), 6.92 (d, 1H, J=7.8 Hz), 6.61 (t, 1H, J=8.0 Hz), 5.90 (d, 1H, 8.0 Hz), 5.70 (s, 2H), 3.57-3.53 (m, 2H), 3.49-3.44 (m, 1H), 2.31-2.28 (m, 1H), 2.12-2.09 (m, 1H), 0.89-0.84 (m, 2H), −0.05 (s, 9H); MS ESI 532.1 [M+H]+, calcd for [C23H26IN3O2Si+H]+ 532.4.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@@H:8]2O)=[CH:4][CH:3]=1.C[CH2:13][N:14](CC)[CH2:15]C.CS(Cl)(=O)=O.CNC>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[N:14]([CH3:15])[CH3:13])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O[C@H]1CCc2ccc(Br)cc21
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCc2ccc(Br)cc21
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of (S)-6-bromo-indan-1-ol (1 mmol) and NEt3 (4 mmol) in dry THF (5 mL) was stirred at −15° C. under argon. A solution of methanesulfonyl chloride (2 mmol) in dry THF (1 mL) was cooled to −78° C. and then added slowly to the alcohol solution maintaining the temperature below 0° C. The reaction mixture was stirred for 2 h at −15° C. and then purged with dimethylamine gas (12 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. Then, it was filtered to remove salts and solvent was evaporated. Crude was used in next step without further purification.
Reaction SMILES: [CH2:1]([S:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].O=S(Cl)[Cl:19]>>[CH2:1]([S:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(C(=O)O)cc1
Product: CCCS(=O)(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
In a manner similar to Preparation 10 react 4-[(1-propylsulfonyl)amino]benzoic acid with SOCl2 to obtain the title compound.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[N:8]=[CH:7]2)[O:4][C@H:3]([CH2:16][OH:17])[C@H:2]1[OH:18]>O>[CH2:1]1[C@@H:5]([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[N:8]=[CH:7]2)[O:4][C@@H:3]([CH2:16][OH:17])[C@@H:2]1[OH:18]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@@H](O)[C@H](CO)O1

Procedure:
αD+26° (c 0.5 water) (commercial 2′-deoxy-D-adenosine-25° (c 0.5 water)).
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C:8]2[C:9]3[CH:27]=[CH:26][C:25]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][C:10]=3[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]O>>[CH3:32][S:29]([O:28][C:25]1[CH:26]=[CH:27][C:9]2[C:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=4)=[CH:34][CH:33]=3)=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[S:11][C:10]=2[CH:24]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: OCc1ccccn1
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCc3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The coupling of the product from Step 2, Example 10 (Methanesulfonic acid 4-[3-(4-hydroxy-benzoyl)-6-methanesulfonyloxy-benzo[b]thiophen-2-yl]-phenyl ester) and pyridin-2-yl-methanol was accomplished by using the procedure outlined in Example 10, Step 3 except stirring for 1 hour instead of 16 hours at room temperature. The solvent was evaporated off and the crude product was chromatographed on silica gel using 1% MeOH/methylene chloride to 2% MeOH/methylene chloride as the gradient eluant to yield the title compound.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].CC(C)([O-])C.[K+].O>CN(C=O)C>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][CH2:10]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 46.5 %

Procedure:
Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.50 g, 1.94 mmol) in DMF (5 mL) was mixed with ethyl acetate (0.38 mL, 3.88 mmol) and potassium tert-butoxide (0.33 g, 2.92 mmol). The mixture was heated to 50° C. for 20 hours. After cooling to room temperature, water was added (50 mL) and the product was extracted with diethyl ether. The ether extract was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluting with heptane-ethyl acetate to provide 4-(2-ethoxycarbonylacetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 47% yield). 1H NMR (300 MHz, CDCl3/TMS): δ=4.20 (q, 2H, J=7.2 Hz), 4.18-4.05 (m, 2H), 3.50 (s, 2H), 2.86-2.70 (m, 2H), 2.68-2.55 (m, 1H), 1.90-1.78 (m, 2H), 1.60-1.50 (m, 2H), 1.45 (s, 9H), 1.28 (t, 3H, J=7.2 Hz). 13C NMR (75 MHz, CDCl3/TMS): δ=204.21, 167.20, 154.67, 79.91, 61.70, 48.93, 47.56, 43.41, 28.73, 27.56, 14.46.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[C:36]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:11]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[C:10]2=[O:28])[CH2:27][CH2:26]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCNCC2)c1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCN(C(=O)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
30 mg of 3-(2-cyanophenyl)-1-(piperidin-4-yl)methyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 2 ml of chloroform. Under ice-cooling, 0.04 ml of triethylamine and 19 mg of benzoyl chloride were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with chloroform, and washed with a saturated aqueous solution of sodium hydrogencarbonate and brine. The organic layer was dried over magnesium sulfate, and then evaporated and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 25 mg of the title compound.
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:18][CH2:17][CH2:16][O:15]3)=[CH:10][CH:9]=2)CCCCC1.[Br:25]C1C=CC(C=O)=CC=1.C(O)CO>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:25][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: c1cc(P(C2CCCCC2)C2CCCCC2)ccc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: Brc1ccc(C2OCCO2)cc1

Procedure:
This is an example of synthesis of ligand 2. 2-(4′-Dicyclohexylphosphinophenyl)-1,3-dioxolane (Ligand 2): Part I. A solution of 4-bromobenzaldehyde (5 g, 0.027 mol), ethylene glycol (7.0 g, 0.11 mmol), and p-toluenesulfonic acid (0.1 g, 0.5 mmol) in benzene was heated at reflux for 24 h using a Dean-Stark setup to remove water. The reaction was taken up in diethyl ether (100 mL) and washed with water (5×30 mL) and brine (30 mL). The organic phase was dried over magnesium sulfate and concentrated under vacuum to afford 2-(4′-bromophenyl)-1,3-dioxolane (5.95 g). Part II. 2-(4′-bromophenyl)-1,3-dioxolane (1.0 g, 4.4 mmol) was dissolved in anhydrous diethyl ether (30 mL) and the solution was cooled to −78° C. t-Butyllithium (5.14 mL, 1.7 M solution in pentane, 8.8 mmol) was added dropwise with stirring. The reaction was stirred for 2 h at −78 ° C. Chlorodicyclohexylphosphine (1.13 g, 4.8 mmol) was added dropwise via a syringe at −78 ° C. with stirring. The reaction mixture was allowed to warm up to room temperature and stirred for an additional 18 h. To the reaction mixture was added argon purged water (25 mL) slowly. The organic phase was separated under argon and the aqueous phase was washed with diethyl ether (20 mL). The combined organic phase was concentrated under vacuum to afford a colorless oil, which was crystallized from methanol to afford ligand 2 as a white crystalline solid having the structure shown below (yield: 1.4 g, 92%). 31P{1H} NMR (CDCl3): δ2.4.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH3:19][NH:20][CH3:21].C([BH3-])#N.[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(O)(=O)C.CO>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:20]([CH3:21])[CH3:19])[CH:12]=2)[CH:3]=1
Reactant: CNC
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 57 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), dimethylamine (2M in methanol, 1.0 mL, 2.0 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[3-(dimethylaminomethyl)phenoxy]benzonitrile fumarate (179 mg, 58%) as a white solid.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@@H:13]1[O:14][CH2:15][CH2:16]2)=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@@H:13]1[O:14][CH2:15][CH2:16]2
Reactant: O=C(N[C@@H]1C(=O)N2CCO[C@H]12)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N2CCO[C@H]12

Procedure:
(5R,6S)-6-benzyloxycarbonylamino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one (950 mg, 3.624 mmole) was hydrogenated with 3 g of 10% palladium on activated carbon in ethyl acetate (80 ml) at 50 psi hydrogen pressure at room temperature for 6 hrs. after removal of catalyst by filtration, deprotected (5R,6S)-6-amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one in ethyl acetate was obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10](I)=[CH:9][C:8]([Br:12])=[C:7]([Cl:13])[N:6]=1)(=[O:3])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)#[CH:15]>C1COCC1.[Cu]I>[C:1]([O:4][C:5]1[C:10]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][C:8]([Br:12])=[C:7]([Cl:13])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1nc(Cl)c(Br)cc1I
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(=O)Oc1nc(Cl)c(Br)cc1C#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
5-bromo-6-chloro-3-iodopyridin-2-yl acetate (14.5 g, 38.5 mmol) was dissolved in THF (50 mL) and cooled to 0° C. TEA (2.5 mL), Copper(I)Iodide (0.514 g, 2.70 mmol), and bistriphenylphosphine palladiumdichloride (0.270 g, 0.385 mmol) were added to the reaction mixture. The mixture was degassed and charged with N2 (3×). Next, 1-ethynyl-4-fluorobenzene (5.55 g, 46.2 mmol) was added drop wise over the course of 1 h at 0° C. The reaction mixture was then allowed to slowly warm to rt and continue to stir for 18 h. LCMS and TLC show the reaction to be incomplete. An additional 2.5 mL of TEA was added. The mixture was then allowed to stir at rt over a long weekend (80 h). At this point, LCMS and TLC show no remaining starting material. The reaction mixture was concentrated to a dry solid. This solid was then taken up in DCM (50 mL) and washed with sat NH4Cl. The aq layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated to >15 g of a brown solid. This solid was dissolved in DCM, adsorbed onto Celite and then flashed on silica gel eluting with a 10-100% DCM in hexanes gradient over 15 column volumes to give 5-bromo-6-chloro-3-((4-fluorophenyl)ethynyl)pyridin-2-yl acetate (11.7 g, 31.7 mmol, 82% yield) as a tan solid. LCMS: m/e 369 (M+H)+ LCMS retention time: 3.74 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 1H), 7.48 (dd, J=8.7 Hz, 2H), 7.09 (dd, J=8.7 Hz, 2H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[N:5][CH:4]=1
Reactant: COc1cnc(-c2ccc(O)cc2)nc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
A mixture of 9.0 g of 5-methoxy-2-(4-hydroxyphenyl)pyrimidine, 8.45 g of benzyl chloride, 270 ml of dimethylformamide (DMF), and 12.3 g of potassium carbonate was stirred at 80° C. for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and distilled to remove ethyl acetate to obtain 8.42 g (percent yield: 64.2%) of 5-methoxy-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]#[CH:10]>C1COCC1.C(OCC)(=O)C>[CH2:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:9]#[CH:8]
Reactant: C1COCCN1
Reactant: C#CCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.3g of morpholine (84 mmol) in 80 mL of THF was slowly added 3-bromo-propyne (5.0 g, 42 mmol). A precipitate formed. The reaction was stirred at room temperature for 1 hour. The reaction mixture was then diluted with 300 mL of ethyl acetate (“EtOAc”), and washed sequentially with 2×200 mL water, and 1×100 mL brine. The organic layer was then dried over MgSO4, and concentrated to yield 4-prop-2-ynyl-morpholine as a light yellow liquid (yield. 50%).
Reaction SMILES: [S:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=[CH:26][CH:25]=1.C(O)C>C(Cl)Cl>[S:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([O:17][CH2:25][CH3:26])=[O:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: c1ccncc1
Reactant: O=C(O)c1cc2c3ccccc3[nH]c(=S)n2n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc2c3ccccc3[nH]c(=S)n2n1

Procedure:
1.5 g (0.006 mole) of 5,6-dihydro-5-thioxopyrazolo-[1,5-c]quinazoline-2-carboxylic acid (prepared as described in Example 1) and 1.26 g (1 equivalent) of phosphorus pentachloride are heated together in 50 ml of methylene chloride at 60° for 30 minutes. The reaction mixture is cooled and the solvent stripped off and replaced with 50 ml of dry pyridine. The solution is treated with 1.1 ml of absolute ethanol and refluxed under N2 for 2 hours.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[ClH:7].Cl.Br[C:10]1[CH:11]=[C:12]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].Cl.[NH2:28][C:29]1[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([O:38][C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[CH3:40])[CH:30]=1>O>[ClH:7].[ClH:7].[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:12]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([NH:28][C:29]3[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([O:38][C@@H:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([F:50])([F:48])[F:49])[CH3:40])[CH:30]=3)[CH:11]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 27.5 °C
Yield: 173 %

Procedure:
K2CO3 (100 g) was dissolved in water (225 mL) and the resulting solution was cooled to 25-30° C. 1-[(3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine dihydrochloride (50.0 g), methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate hydrochloride (53.7 g) and 2-methyl THF (250 mL) were added and the mixture was stirred until complete dissolution had taken place. The layers were separated, retaining the organic phase. 2-Methyl tetrahydrofuran (40 mL) was added and the mixture was distilled under reduced pressure to a volume of 350-400 mL. Xantphos (2.32 g, 3 mol %) was added, followed by cesium carbonate (48.0 g) and tris(benzylideneacetone)dipalladium(0) (1.84 g, 1.5 mol %). The reaction mixture was heated to 70-75° C. until judged complete by HPLC and then cooled to 20° C. Water (250 mL) was added and the mixture stirred to dissolve the inorganics. The mixture was filtered through celite, then the phases allowed to separate. The aqueous phase was discarded. The celite was washed with MeOH (200 mL). The MeOH wash was added to the previous organic phase. The mixture was slowly added to 5 M aqueous HCl over approximately 40 minutes. The resulting crystalline slurry was stirred overnight at room temperature, then filtered, washing with MeOH (100 mL, cooled to 0° C.) and dried under reduced pressure to give the title compound (72.8 g, 87% th) as orange to red crystalline sold.