Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][C:4](OC)=[O:5].C[O-].[Na+].[CH3:12][NH:13][C:14]([NH2:16])=[S:15]>CO>[CH3:12][N:13]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:8])[N:16]=[C:14]1[SH:15]
Reactant: CNC(N)=S
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(=O)n(C)c(S)n1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Methyl 3-oxobutanoate (2 mL, 18.5 mmol) was added dropwise to a solution of sodium methoxide (25% wt in MeOH, 5 mL) and anhydrous MeOH (20 mL). N-methyl thiourea (1.67 g, 18.5 mmol) was added to the reaction mixture. The resulting solution was stirred at reflux for 5 hours. After cooling to room temperature, the solvent was evaporated. The residue was dissolved in water (25 mL), and the solution was acidified to pH 2-3 with concentrated HCl. The solid material was recovered by filtration, washed with water (2×20 mL) and diethyl ether (1×30 mL), and dried in vacuo, affording 3,6-dimethyl-2-sulfanyl-3,4-dihydropyrimidin-4-one (2.16 g, 73% yield). The product was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([F:36])=[C:17]([C@:19]34[O:27][CH2:26][CH2:25][C@H:24]3[CH2:23][S:22][C:21]([NH:28]C(=O)OC(C)(C)C)=[N:20]4)[CH:18]=2)=[O:11])=[N:8][CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:21]1[S:22][CH2:23][C@@H:24]2[CH2:25][CH2:26][O:27][C@:19]2([C:17]2[CH:18]=[C:13]([NH:12][C:10](=[O:11])[C:7]3[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:37])[F:1])=[CH:9][N:8]=3)[CH:14]=[CH:15][C:16]=2[F:36])[N:20]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(OC(F)F)cn4)ccc3F)OCC[C@H]2CS1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(OC(F)F)cn4)ccc3F)OCC[C@H]2CS1
Yield: 145.1 %

Procedure:
A solution of tert-butyl ((4aR,7aR)-7a-(5-(5-(difluoromethoxy)picolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.011 mmol) and TFA (17.17 μL, 0.223 mmol) in DCM (111 μL) was stirred at rt for 3 h, and the solvents were removed to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(difluoromethoxy)picolinamide (7 mg) as its TFA salt as a colorless oil. 1H NMR (500 MHz, METHANOL-d4) 8.60 (br. s., 1H), 8.29 (br. s., 1H), 8.18 (dd, J=7.1, 2.7 Hz, 1H), 7.94-7.87 (m, 1H), 7.84 (dd, J=8.6, 1.6 Hz, 1H), 7.31-7.22 (m, 1H), 7.10 (t, J=75 Hz, 1H), 4.33-4.19 (m, 2H), 3.46 (dd, J=13.6, 3.8 Hz, 1H), 3.34-3.25 (m, 1H), 3.18-3.09 (m, 1H), 2.32 (q, J=7.0 Hz, 2H). MS (M+H)+: 439.11.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[Cl:24][C:25]1[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27](Cl)=[O:28].CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O.O>[Cl:24][C:25]1[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1)=[O:28]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1)c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Compound 137 (40 mg, 0.13 mmol), 2,5-dichloro-nicotinoyl chloride (28 mg, 0.13 mmol), and DIEA (0.02 mL, 0.13 mmol) were suspended in dioxane (2 mL), and stirred overnight at room temperature. The reaction mixture was diluted with EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc/H2O, and dried under vacuum to provide 180 (40 mg, 64% yield) as a white solid. LC-MS (M+H=478, obsd.=478).
Reaction SMILES: [K+].[CH2:2]([C@@H:5]1[O:7][C@H:6]1[C:8]([O-:10])=O)[CH2:3][CH3:4].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CC(C)=O.C1(C)C=CC=CC=1.O>[CH:25]1([NH:28][C:8]([C@H:6]2[C@H:5]([CH2:2][CH2:3][CH3:4])[O:7]2)=[O:10])[CH2:27][CH2:26]1
Reactant: CCC[C@@H]1O[C@H]1C(=O)[O-]
Reactant: NC1CC1
Agent: CC(C)(C)C(=O)Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC[C@@H]1O[C@H]1C(=O)NC1CC1
Temperature: 3 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
200 g of trans-3-n-propyloxiranecarboxylic acid potassium salt are suspended in 2 l of acetone, admixed with 120 g of triethylamine and cooled to 3° C. 146 g of pivaloyl chloride are then added, and the mixture is stirred at 20° C. for 20 minutes and then cooled to 3° C. To this are added 82 g of cyclopropylamine in 175 ml of acetone. After stirring for 20 min, the solution is drawn off in vacuo, and the residue is dissolved in 2 l of toluene and 400 ml of water, and the pH is adjusted to 10. The aqueous phase is removed and the organic phase is admixed with 300 ml of water and the pH is adjusted to 2 with hydrochloric acid. The organic phase is removed and concentrated in vacuo. 175 g of N-cyclopropyl-trans-3-n-propyloxiranecarboxamide are obtained as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:5]2.C(=O)([O-])O.[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:3]=3)[CH2:7]2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CNc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 4 h
Yield: 76.8 %

Procedure:
Into a solution of 0.5 g of 5-amino-2-(4-chlorophenyl)sulfonylaminoindan in 5 ml of hexamethylphosphoric triamide are added 0.2 g of sodium hydrogen carbonate and 0.25 g of methyl bromoacetate at 5 to 10° C., and the mixture is stirred at the same temperature for 4 hours. Water is added to the reaction mixture, followed by extraction with ethyl acetate. The extract is washed, dried and the solvent is evaporated. The residue is purified by separation through silica gel column chromatography (eluant: chloroform : ethyl acetate=7 : 3), and further recrystallized from ethyl acetate-n-hexane mixture to give 0.47 g of methyl N-[2-(4-chlorophenyl)sulfonylaminoindan-5-yl]glycinate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].CC1C(C)=CC(C)=CC=1[OH:20]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:20])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: Cc1cc(C)c(C)c(O)c1
Product: Cc1cc(O)c(C)c(C)c1O

Procedure:
By following in the same manner as in Example 63, except that 100 g. (735 m. moles) of 2,3,6-trimethylphenol were used instead of 2,3,5-trimethylphenol, 2.05 g. (13.5 m. moles) of 2,3,6-trimethylhydroquinone were obtained. The yield of dihydric alkylphenol was 29.4 percent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]([CH3:21])([CH3:20])[CH2:7][CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:2].O.NN>C(O)C>[CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]([CH3:21])([CH3:20])[CH2:7][CH2:8][NH2:9])[CH3:2]
Reactant: CCOC(=O)NC(C)(C)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)NC(C)(C)CCN
Yield: 95.5 %

Procedure:
5.12 g of ethyl[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,1-dimethylpropyl]-carbamate are put into solution in 47 mL of ethanol. 4 mL of hydrazine hydrate are added and the mixture is refluxed for 30 minutes with heating. After returning to RT, the reaction medium is filtered and the solvent is then evaporated. 2.8 g (yield=88%) of ethyl(3-amino-1,1-dimethylpropyl)carbamate are obtained as a brown gum used as such.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1Br)=[O:14].CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.[Zn].Cl[Ni](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>[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:14]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)c1ccncc1Br
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccncc1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4mL) was added slowly over ~3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then 3-bromopyridin-4-carboxylic acid methyl ester (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40°-45° C. The mixture was cooled and distributed between EtOAc (100 ml) and 5% aqueous citric acid (50 mL). The organic layer was washed with H2O (2×50 mL), dried with Na2 SO4. After evaporation of the solvent the residue was purified on silica gel, eluting with 35% EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+1) 253.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.[F:30][C:31]([F:35])([F:34])[CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:30][C:31]([F:35])([F:34])[CH2:32][O:17][C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
Di-tert-butyl azodicarboxylate (2.96 g, 12.83 mmol) was added to an ice cooled mixture of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (2 g, 10.70 mmol), 2,2,2-trifluoroethanol (10.70 g, 106.95 mmol) and triphenylphosphine (3.37 g, 12.83 mmol) in THF (24 mL). The mixture was stirred at 70 C for 16 h. The mixture was concentrated under vacuum and the residue was purified by FCC, eluting with a gradient of EtOAc in heptane. The white solid collected was washed with heptane and the filtrate was concentrated to afford the title compound (1.263 g, 44%), which was used without further purification. Method B HPLC-MS: MH+ requires m/z=270 Found: m/z=214 (M minus tert-butyl), Rt=2.02 min (82%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: BrCCOC1CCCCO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.20 g, 1.0 mmol) (Aldrich Cat. No. 525057), 2-(2-bromoethoxy)tetrahydro-2H-pyran (170 μL, 1.1 mmol) (Aldrich Cat. No. 475394) and potassium carbonate (0.21 g, 1.5 mmol) in acetonitrile (2 mL) was stirred at r.t. overnight. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[Cl:22])(=[O:10])=[O:9].N(OC(C)(C)C)=O>CC(O)=O>[Cl:22][C:17]1[C:16]2[C:21](=[C:12]3[C:13](=[CH:14][CH:15]=2)[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[S:8](=[O:10])(=[O:9])[NH:11]3)[N:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2c(Cl)ccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3c(Cl)ccnc23)-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.5 %

Procedure:
2-Amino-N-(4-chloro-quinolin-8-yl)-benzenesulfonamide (Intermediate 275) (1.3 g, 3.89 mmol) was dissolved in AcOH (13 ml) and the mixture was stirred at 0° C. for 5 min. The solution was cooled to −10° C. and t-butyl nitrite (0.7 ml, 5.83 mmol) was added dropwise and the mixture was stirred at room temperature 30 min. The mixture was quenched with sat. NaHCO3 solution and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (400 mg, 33%) after the purification by column chromatography with DCM/MeOH (90:10) as the eluent.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCC(CO)CC1
Yield: 15.6 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from Example 16C was reacted with 4-piperidinemethanol (135 mg, 1.17 mmol) according to the procedure described in Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (36 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (brs, 1H), 9.10 (brs, 1H), 8.55 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.37-7.43 (m, 2H), 7.27 (m, 1H), 6.97 (m, 1H), 6.48 (s, 1H), 4.20-4.50 (m, 3H), 3.99 (s, 3H), 3.23 (m, 2H), 2.96-3.00 (m, 2H), 2.74-2.78 (m, 2H), 2.01-2.05 (m, 2H), 1.61-1.65 (m, 2H), 1.27 (s, 9H), 1.00-1.15 (m, 2H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: [C:1]([O:11][Si](C)(C)C)(=O)[CH2:2][C:3]([O:5][Si](C)(C)C)=[O:4].C([Li])CCC.[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH2:25]C.C(=O)(O)[O-].[Na+]>C(OCC)C>[O:11]=[C:1]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: C[Si](C)(C)OC(=O)CC(=O)O[Si](C)(C)C
Reactant: CCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCC(=O)CC(=O)O
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A stirred solution of bis-trimethylsilyl malonate (21.6 g, 71.5 mmol) in 100 mL of anhydrous diethyl ether was cooled to −78° C. To this solution, n-butyl lithium (1.6 M in ether, 44.7 mL, 71.5 mmol) was added slowly, keeping the temperature below −60° C. Upon completion of addition, the reaction was allowed to warm to −10° C., at which time hexanoyl chloride (5 mL, 35.75 mmol) was added quickly and allowed to stir for 30 minutes. Next, 150 mL of a cold, aq. 5% sodium bicarbonate solution was added, and the resulting solution was stirred vigorously for 30 minutes. The aq. layer was separated out and acidified with cold 4N sulfuric acid until pH=2. The aq. layer was then extracted 2×50 mL with diethyl ether, dried over MgSO4, and concentrated down in vacuo to afford a white solid. This solid could be further purified by recrystallization from hexane, if necessary. 4.9 g, 87% yield. 1H NMR (300 MHz, CDCl3) δ=3.49 (s, 2H, CH2), 2.59 (t, 2H, J=7.3 Hz, CH2), 1.64 (p, 2H, J=7.4 Hz, CH2), 1.34 (m, 4H, CH2CH2), 0.92 (t, 3H, J=6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ=204.4, 182.8, 87.9, 48.1, 43.4, 31.3, 23.5, 14.1 ppm.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[N+:2]=[N-:3].[C:10]([C:12]1[N:17]=[C:16]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[CH:14][CH:13]=1)#[CH:11].[Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>O.C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:1]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]4[N:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:15]=[CH:14][CH:13]=3)[N:3]=[N:2]2)[CH:5]=1
Reactant: [N-]=[N+]=Nc1cccnc1
Reactant: C#Cc1cccc(-c2ncccn2)n1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: c1cnc(-c2cccc(-c3cn(-c4cccnc4)nn3)n2)nc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 10.4 %

Procedure:
100 mg (833 μmol) of 3-azidopyridine (for preparation see U.S. Pat. No. 4,775,762, CAUTION explosive!) and 151 mg (833 μmol) of 2-(6-ethynylpyridin-2-yl)pyrimidine were initially charged in a mixture of 1 ml of water and 1 ml of tert-butanol, 16.5 mg (83.3 μmol) of the sodium salt of L-ascorbic acid and 20.8 mg (83.3 μmol) of copper(II) sulfate pentahydrate were added, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was then added to water and extracted repeatedly with dichloromethane. The separated organic phases were then dried over magnesium sulfate, filtered and concentrated. Chromatographic purification gave 26.0 mg (10% of theory) of 2-{6-[1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl]pyridin-2-yl}pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(S)CCCCCCCCCCC.C[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: COc1cccc(N)c1C(=O)NCc1ccccc1
Agent: CCCCCCCCCCCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(O)c1C(=O)NCc1ccccc1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
To a solution of 2-amino-N-benzyl-6-methoxybenzamide (0.228 g, 0.89 mmol, 1.0 equiv) in 3 mL of anhydrous DMF was added 1-dodecanethiol (0.360 g, 1.78 mmol, 2.0 equiv), followed by adding NaOMe (0.385 g of 25% solution in MeOH, 1.78, 2.0 equiv). The mixture was heated in a microwave at 150° C. for 10 min. The mixture passed through a silica gel plug, which was washed with an ethyl acetate-methanol mixture (1:1). The crude product was purified by PL-SO3H MP SPE (Varian) to give 2-Amino-N-benzyl-6-hydroxybenzamide (0.176 g, 82%) as thick oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.55-4.20 (vb.s., 2H), 4.60 (s, 1H), 4.61 (s, 1H), 6.25 (d, J=7.8 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 7.16-7.52 (m, 5H), 8.58 (br. s., 1H), 12.05 (br. s., 1H); HPLC: tR=3.97 min, UV254=98%; HRMS (ESI): m/z calcd for C14H14N2O2 [M+1]+ 243.11. found 243.1134.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=O.[C:11]([C:14]1[CH:15]=[C:16]2[C:21](=CC=1O)[N:20]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:18][C:17]2=[O:30])(=[O:13])[CH3:12].[O-]CC.[Na+].C(Cl)(Cl)Cl>C(O)C.Cl.O>[O:30]=[C:17]1[C:16]2[C:21](=[CH:6][C:5]3[O:4][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[CH:12][C:11](=[O:13])[C:14]=3[CH:15]=2)[N:20]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:18]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)c1nc2cc(O)c(C(C)=O)cc2c(=O)[nH]1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1nc2cc3oc(C(=O)OCC)cc(=O)c3cc2c(=O)[nH]1
Yield: 73 %

Procedure:
A mixture of diethyl oxalate (4.4 ml) and the product of step (a) (1.1 g; 3.98 mmole) in ethanol (50 ml) was added slowly to freshly prepared sodium ethoxide (0.68 g; 9.99 mmole) in ethanol (80 ml) to give instantly a yellow suspension. After the addition, the mixture was heated to reflux on the steambath for half an hour to give a brown suspension. The mixture was cooled and neutralised with dilute hydrochloric acid to give a bright orange precipitate. This was extraced into chloroform, dried and evaporated to give a bright orange solide. The solid was redissolved in ethanolic hydrogen chloride. The solution was heated to reflux on a steambath for 3 hours. The mixture was cooled and was treated with water. After concentration, this was extracted into chloroform. The organic extract was washed with water, dried and evaporated to give a brown solid (0.95 g, 73%) whose structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].[CH3:10][C:11]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C@H:19](O)[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CCCC(C)C.C(OCC)(=O)C>[CH3:13][C:11]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C@@H:19]([S:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)([CH3:10])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)c1nccs1
Reactant: Sc1cc(Cl)ccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCC(C)C
Product: CC(C)(C)OC(=O)NCC[C@@H](Sc1cc(Cl)ccc1Cl)c1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
To a solution of 2,5-dichlorothiophenol (179 mg, 1 mmol), [(3S)-3-hydroxy-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethyl ester (258 mg, 1 mmol) and triphenylphosphine (315 mg, 1.2 mmol) in dry tetrahydrofuran (30 ml) at 0° C. under nitrogen, was added diisopropyl azodicarboxylate (243 mg, 0.24 ml, 1.2 mmol) dropwise over 5 minutes. The mixture was stirred at room temperature for 16 h, then concentrated in vacuo to leave a crude yellow gum. Flash chromatography (silica, 15% ethyl acetate in isohexane) afforded a clear oil (85 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:20][C:5]1[CH:4]=[C:3]([Cl:21])[C:2]([NH:1][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][C:6]=1[C:8]1[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2Cl)c1=O
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of 0.35 g of 3-(5-amino-2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-334) and 3.1 ml of ethyl chloroformate was stirred at 100° C. for 2 hours. After completion of the reaction, the reaction mixture was left cooling to room temperature, and the excess ethyl chloroformate was distilled out under reduced pressure. The residue was recrystallized from hexane, which afforded 0.32 g (yield, 79%) of 3-(2,4-dichloro-5-ethoxycarbonylaminophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-346; m.p., 116.2-C).