Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].O=[C:20]1[CH2:24][CH2:23][S:22][CH:21]1[C:25]([O:27][CH3:28])=[O:26]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:20]2[CH2:24][CH2:23][S:22][C:21]=2[C:25]([O:27][CH3:28])=[O:26])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)C1SCCC1=O
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Product: COC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CCS1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and methyl 3-oxotetrahydrothiophene-2-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(methoxycarbonyl)-4,5-dihydro-thien-3-yl]ureido}-benzoate, m.p. 161°-163° C.,
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6](=[O:8])[CH:7]=1.[CH3:15][Si](C)(C)N[Si](C)(C)C.[Li].CI>O1CCCC1>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6](=[O:8])[CH:7]=1
Reactant: CCOC(=O)Cn1ncc(C)cc1=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)n1ncc(C)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To ethyl [4-methyl-6-oxopyridazin-1(6H)-yl]acetate (0.132 g, 0.673 mmol) in tetrahydrofuran (4 mL) at −78° C. was added 1M lithium hexamethyldisilazane solution (0.74 mL). The reaction mixture was stirred at −78° C. for 15 min then was added methyl iodide (0.046 mL, 0.74 mmol). After being stirred at −78° C. for 2 h, the reaction mixture was allowed to warm to ambient temperature over 0.5 h. Removal of the volatiles in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl 2-[4-methyl-6-oxopyridazin-1(6H)-yl]propanoate as oil. To 88 mg (0.42 mmol) of the above oil in tetrahydrofuran (0.3 mL), water (0.2 mL) and methanol (0.2 mL) was added 5 N sodium hydroxide solution (0.2 mL). The reaction mixture was stirred at ambient temperature for 3 h then neutralized with 2 N hydrochloric acid and purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. LC/MS 183.2 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Br:16])[CH2:9][CH2:8][C:7]1=[O:17].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Br:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH:7]([OH:17])[CH2:8][CH2:9]2
Reactant: COC(=O)CCC1C(=O)CCc2cccc(Br)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCC1c2c(Br)cccc2CCC1O
Temperature: 0 °C
Yield: 102.4 %

Procedure:
A solution of 8-bromo-1,2,3,4-tetrahydro-2-oxo-naphthalenepropionic acid methyl ester (B-2, 31.12 g, 0.100 mol) in diethylether (100 mls) was added to an ice-cooled suspension of lithium aluminum hydride (8.0 g, 0.21 mol) with stirring. The cold bath was removed, and the mixture was stirred at room temperature for 2 hours. The mixture was cooled in ice, and water (8.0 mls), 15% NaOH (8.0 mls), and water 24.0 mls) were added in succession. The mixture was stirred at room temperature for two hours and filtered. The precipitate was washed with tetrahydrofuran, and the combined flitrate was dried (MgSO4, and the solvent was removed under vacuum to leave the title compound as an oil (B-3, 29.2 g, 100%). NMR (CDCl3, TMS) δ1.35 (m, 1H), 1.7-2.1 (M,5H), 2.7-3.15 (m, 3H), 3.35-3.45 (m, 1H), 3.45-3.57 (m, 1H), 3.57-3.82 (m,2H), 4.0-4.15 (m,1H), 6.9-7.1 (m,2H), 7.38 (dd, 1H). IR (Major peaks) 3345, 3055, 1591, 1559, 1454, 1433, 1060, 767. Mass spec. m+at m/z 284, 285.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][CH:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:21][CH:17]([CH3:16])[C:18]#[C:19][CH3:20])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CC#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)Oc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 135 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 60 mg of 3-pentyn-2-ol, to which 29 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 130 mg of 4-(2,3-difluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (167)).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][O-:16].[Na+].O>CN(C)C=O>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 4′-fluoro-3′-trifluoromethylacetophenone (25.0 g) in N,N-dimethylformamide (70 ml) was added under ice-cooling sodium methoxide (7.21 g), and the mixture was stirred under ice-cooling for 2 hr and further at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (24.3 g) as a brown solid.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](Cl)=[O:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:22])[CH2:20][CH3:21]>C(Cl)Cl>[CH2:19]([NH:22][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=1)=[O:17])[CH2:20][CH3:21]
Reactant: CCCN
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc2c1OCC2(C)C
Solvent: ClCCl
Product: CCCNC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2

Procedure:
To a solution of (7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl) carboxylic acid chloride (450 mg, 1.69 mmol) in CH2Cl2 (10 mL) is added in a single portion n-propylamine (2 mL). After the exothermic reaction subsides, the mixture is evaporated and suspended in 1N HCl (10 mL). The insoluble material is filtered and crystallized from isopropanol/H2O, to yield N-propyl (7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)carboxamide as white needles.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[H][H]>C(O)C.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:35])=[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]4)[C:13]=3[O:12]2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OC(Cc2c[nH]c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.030 g, 0.063 mmol) obtained in Example A11, Step 1 in ethanol (2.0 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.027 g) under an argon atmosphere, and then the inside of the reaction vessel was replaced with hydrogen. The reaction mixture was stirred at room temperature for 4 hours, and then filtered through Celite, and the solvent was evaporated under reduced pressure to obtain tert-butyl 4-({2-[(1H-indol-3-yl)methyl]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.028 g, 93%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.B(Br)(Br)Br>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1
Reactant: COc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(O)c3)c2n1
Yield: 99.9 %

Procedure:
A solution of 7-(2-furyl)-3-(3-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (119 mg, 0.37 mmol) in dichloromethane (20 mL) at 0° C. was treated with boron tribromide (1-M in dichloromethane, 8.8 mL, 8.8 mmol) portion-wise over 3 days, concentrated in vacuo and isolated by filtration to give the title compound (114 mg, 100%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[N:8][OH:9])=[CH:4][CH:3]=1.[CH2:10]([OH:13])[CH:11]=[CH2:12]>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:12][CH:11]([CH2:10][OH:13])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Br)s1
Reactant: C=CCO
Solvent: C1CCOC1
Product: OCC1CC(c2ccc(Br)s2)=NO1
Reaction time: 4 h

Procedure:
5-Bromo-thiophene-2-carbaldehyde oxime (40.2 g, 195.2 mmol) and allyl alcohol (32.4 ml) were added to tetrahydrofuran (200 ml) and then bleach (1318 ml) was added. The reaction was stirred for four hours followed by extraction with tetrahydrofuran (2×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (19 g).
Reaction SMILES: CS([CH:5]([OH:20])[C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=O)=O.[C:21]([O-])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+].O>CN(C=O)C>[C:21]([CH:5]([OH:20])[C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])c1ccccc1
Reactant: Cc1cn([C@H]2C=C[C@@H](C(O)S(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn([C@H]2C=C[C@@H](C(O)C(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of 5'-mesyl-d4T (6, 0.4 g) in 6 ml of DMF was added powdered sodium benzoate (0.24 g). The reaction was stirred at 100° C. for 6 hours. After cooling, water (30 ml) was added. The resulting precipitate was filtered, washed with 2×5 ml water and dried to give 5'-benzoly-d4T (7'), 0.04 g (91%).
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[N:26]=[CH:27][C:28]=2[CH:29]([CH3:31])[CH3:30])=[CH:18][C:17]=1[CH3:40])C)(C)(C)C>ClCCl>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[N:25]1[C:24]([CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH:14][CH3:13])=[C:17]([CH3:40])[CH:18]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[CH:27]=[N:26]1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of 4.0 M HCl in 1,4-dioxane (2.8 mL, 11.0 mmol) is added to a solution of {4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-carbamic acid tert-butyl ester (1.85 g, 3.7 mmol) in dichloromethane (25.0 mL) at 0° C. The reaction mixture is then stirred at room temperature for 2.0 h. The solvents are removed by evaporation under reduced pressure. The residue is partitioned between EtOAc (50 mL) and 5% aqueous sodium bicarbonate (30 mL). The organic layer is washed with brine (40 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography (EtOAc/Hexane) to afford the title compound as a foamy solid (1.25 g, 84%). LC-ES/MS m/e 404.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][OH:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:26][C:27]#[N:28].[Na+].[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]([N:9]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([OH:15])[C:27]([NH2:28])=[O:26])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: N#C[O-]
Reactant: Cc1cnc(N(CCCCNO)C2CCCc3cccnc32)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(N(CCCCN(O)C(N)=O)C2CCCc3cccnc32)c(C)c1

Procedure:
N-{4-[(3,5-Dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-hydroxylamine (HBr salt) (180 mg, 0.25 mmol) was dissolved in H2O (2.5 mL) and treated with sodium cyanate (65 mg, 1.0 mmol) for 2 hours. 15% aqueous NaOH solution (0.1 mL) was added and the aqueous was extracted with CH2Cl2 (3×5 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure to afford, after radial chromatographic purification on a silica gel plate (3% NH4OH/CH3CN)N-{4-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-N-hydroxyurea (73 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=1
Reactant: Cc1ccc(F)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cn1
Reaction time: 2.5 h
Yield: 35 %

Procedure:
2-fluoro-5-methylpyridine in an amount of 500 mg (4.50 mmol) was dissolved in 50 mL of carbon tetrachloride, following which 1.20 g (6.76 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added and refluxing under heating was carried out for 2.5 hours. Following reaction completion, the reaction mixture was returned to room temperature, the solvent was removed by distillation under reduced pressure, and purification was carried out by silica gel column chromatography (hexane/ethyl acetate=19:1), giving 300 mg of 5-bromomethyl-2-fluoropyridine (yield, 35%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:16])[CH3:15])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
At −78° C. a 2.5 M solution of n-butyl lithium (18.6 mL, 46.4 mmol, 1.1 equiv) was added dropwise to 2,6-dibromopyridine (1) (10.0 g, 42.2 mmol, 1.0 equiv) in THF (780 mL). The solution was then stirred for 20 min at which point acetophenone (5.06 g, 44.3 mmol, 1.0 equiv) was added. The reaction was allowed to stir an additional 0.5 hr at −78° C., at this time the cooling bath was removed and the reaction allowed to warm room temperature. The reaction was stirred at room temperature for 1 hr and quenched with saturated sodium bicarbonate (250 mL). The layers were separated and the aqueous layer extracted with dichloromethane (250 mL). The combined organic layers were dried over sodium sulfate and absorbed onto silica gel (30 g) by concentration under reduced pressure. This material was then purifies on a silica gel column (300 g) by eluting with heptanes (1 L), ethyl acetate (2%) in heptanes (2 L), ethyl acetate (5%) in heptanes (2 L) and finally ethyl acetate (10%) in heptanes (1 L). The desired product was isolated pure in 40% yield (4.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28](=[O:34])[NH:29][CH2:30][CH2:31][CH2:32]O)([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:23]([O:27][C:28]([NH:29][CH2:30][CH2:31][CH2:32][N:15]([C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:34])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1cccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To an ice cold solution of tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (500 mg, 1.611 mmol), tert-butyl(3-hydroxypropyl)carbamate (282 mg, 1.611 mmol) and triphenylphosphine (634 mg, 2.417 mmol) dissolved in THF (16 mL) was added DIAD (470 μl, 2.417 mmol) and stirred for 16 h. The reaction mixture was concentrated in vacuo and the crude residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (600 mg, 80%). LCMS: Rt=1.02 min, m/z=468.4 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Reactant: CSc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Oc3ccnc(C(=O)OC(C)(C)C)c3)cc2s1
Temperature: 75 °C
Reaction time: 6 h
Yield: 61.4 %

Procedure:
To a solution of 2-(methylthio)benzo[d]thiazol-6-ol (5.0 g, 25.38 mmol, 1.0 eq) in 25 mL of N,N-dimethylformamide was added tert-butyl 4-chloropicolinate (8.13 g, 38.07 mmol, 1.5 eq) and cesium carbonate (20.67 g, 63.45 mmol, 2.5 eq). The reaction mixture was stirred at 75° C. for 6 hours. After the mixture was cooled to room temperature, the mixture was added 120 mL of water and aqueous phase extracted with ethyl acetate (3×150 mL), combined organic layers were dried over sodium sulfate. After filtration, the solid was purified by silica gel column eluted with ethyl acetate-hexane 0%-50% mixture to give 5.84 g of the titled compound as brown powder (62%). MH+=375.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[N:7]=[C:6](C(Cl)(Cl)Cl)[N:5]=2)[CH2:3][CH2:2]1.[NH3:18]>O1CCCC1.O>[NH2:18][C:6]1[N:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=[C:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[N:7]=1
Reactant: N
Reactant: ClC(Cl)(Cl)c1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1

Procedure:
71.2 g of 2-cyclopropyl-4,6-bis-trichloromethyl-1,3,5-triazine are dissolved in 70 ml of tetrahydrofuran, and at room temperature are added, with stirring, 300 ml of a concentrated aqueous ammonia solution. The reaction mixture is stirred for 30 minutes; it is then diluted with water, and the formed emulsion is extracted with ether. The ether phases are collected, dried, filtered and subsequently concentrated by evaporation. The residue crystallises and there remain 48 g of the crystalline title product, m.p. 111°-114° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[F:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=1[CH:24]=[CH:25][CH2:26]Cl>>[F:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=1[CH:24]=[CH:25][CH2:26][N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1
Reactant: Fc1ccc(C=CCCl)c(F)c1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(F)cc2F)c1=O
Yield: 92 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 2,4-difluorocinnamyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 92.0%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@@H:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C@@H:8]([CH3:17])[C:9]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32](=[O:36])[N:33]([CH3:35])[CH3:34]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[S:6][C:5]([C@@H:7]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C@@H:8]([CH3:17])[C:9](=[O:10])[NH:11][C:12]3[S:13][CH:14]=[N:15][N:16]=3)=[CH:4][CH:3]=2)[CH:29]=[CH:30][C:31]=1[C:32]([N:33]([CH3:35])[CH3:34])=[O:36]
Reactant: C[C@@H](C(=O)Nc1nncs1)[C@H](c1cccc(F)c1)c1ccc(Br)s1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1Cl
Product: C[C@@H](C(=O)Nc1nncs1)[C@H](c1cccc(F)c1)c1ccc(-c2ccc(C(=O)N(C)C)c(Cl)c2)s1

Procedure:
In a similar manner to Example 43, the Suzuki coupling reaction of the title compound of Example 97, (2R,3R)-3-(5-bromothiophen-2-yl)-3-(3-fluorophenyl)-2-methyl-N-(1,3,4-thiadiazol-2-yl)propanamide (240 mg, 0.563 mmol), and 3-chloro-4-(dimethyl-carbamoyl)phenylboronic acid (256 mg, 1.126 mmol) afforded the title compound of Example 110 (147 mg, 0.278 mmol, 49.4% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.96 (1H, s) 7.71 (1H, d, J=1.51 Hz) 7.61 (1H, dd, J=7.93, 1.64 Hz) 7.39 (1H, d, J=3.78 Hz) 7.33 (1H, d, J=8.06 Hz) 7.19-7.28 (2H, m) 7.15 (1H, dd, J=10.07, 2.01 Hz) 7.11 (1H, d, J=3.78 Hz) 6.83-6.89 (1H, m) 4.51 (1H, d, J=1.33 Hz) 3.48-3.57 (1H, m) 3.11 (3H, s) 2.91 (3H, s) 1.32 (3H, d, J=6.55 Hz). LC/MS (m/z) 529.11 (M+H)+]; HPLC Rt: 3.448 min.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][N:27]=2)=[CH:19][CH:18]=1.[C:36](O)(=[O:42])/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[C:36]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][N:27]=2)=[CH:21][CH:22]=1)(=[O:42])/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)s1
Reactant: CCC/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1ccc(-c2ncc(CCCCCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Dicyclohexylcarbodiimide (0.2 g) is added to a solution of 2-(4-hydroxyphenyl)-5-octylthiazole (0.25 g), (E)-hex-2-enoic acid, (0.1 g) 4-(dimethylamino)pyridine (0.05 g) and dichloromethane (20 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (9/1 v/v) as eluent and recrystallisation from hexane to yield 0.15 g of 2-(4-[(E)-hex-2-enoyloxy]phenyl)-5-octylthiazole.