Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:5])(O)[CH3:3].C(P(CCCC)CCCC)CCC.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:59]=[CH:60][C:61]=1[O:62][CH3:63])[CH2:38][N:39]1[C:48](=[O:49])[C:47]2[C:42](=[CH:43][C:44]([F:51])=[C:45]([OH:50])[CH:46]=2)[N:41]([CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[C:40]1=[O:58]>C1COCC1>[F:1][CH:2]([F:5])[CH2:3][O:50][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][C:44]=1[F:51])[N:41]([CH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)[C:40](=[O:58])[N:39]([CH2:38][C:37]1[CH:59]=[CH:60][C:61]([O:62][CH3:63])=[C:35]([O:34][CH3:33])[CH:36]=1)[C:48]2=[O:49]
Reactant: CC(O)(F)F
Reactant: COc1ccc(Cn2c(=O)c3cc(O)c(F)cc3n(C3CCOCC3)c2=O)cc1OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cc(OCC(F)F)c(F)cc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
0.125 g of difluoroethanol, 0.47 g of tributylphosphine and 0.38 g of DIAD are successively added to a solution of 0.4 g of the compound obtained in Step 4.7 in 15 ml of THF. This mixture is stirred overnight at room temperature. The reaction medium is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (100/0, v/v) to (30/70) to give 0.38 g of the expected product.
Reaction SMILES: [C:1]1([C:7]([OH:11])([CH3:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[OH:11][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:10])[CH:8]=[O:9]
Reactant: CC(O)(CO)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)(C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a solution of 2-phenylpropane-1,2-diol (3 g, 19.7 mmol) in DCM (60 mL) was added Dess-Martin periodinane (8.36 g, 19.7 mmol) at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature. After completion of the reaction (monitored by TLC (TLC eluent: 30% EtOAc in petroleum ether)), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layers were combined and washed with water, washed with saturated NaCl solution, and dried on anhydrous Na2SO4. The organic layer was then filtered and concentrated under vacuum to yield intermediate 2-hydroxy-2-phenylpropanal (2 g unpurified) as a colorless liquid. The intermediate thus obtained was used in the next step without any further purification. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H). The 1H NMR spectrum was not completely clean, but since the aldehyde peak at 9.50 ppm was observed, this intermediate was used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[S:10][C:9]([N:11]([CH3:15])[C:12](Cl)=[O:13])=[N:8][C:7]=1[CH3:16])(=[O:5])=[O:4].C(N(CC)CC)C.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>O1CCOCC1>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[S:10][C:9]([N:11]([CH3:15])[C:12]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[CH:37][CH:36]=2)=[O:13])=[N:8][C:7]=1[CH3:16])(=[O:5])=[O:4]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1nc(N(C)C(=O)Cl)sc1S(=O)(=O)N(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc(N(C)C(=O)Nc2ccc(N3CCOCC3)cc2)sc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
12.0 g (40.3 mmol) of 5-[(dimethylamino)sulphonyl]-4-methyl-1,3-thiazol-2-yl(methyl)carbamoyl chloride and 4.08 g (40.3 mmol) of triethylamine were dissolved in 150 ml of dioxane, and 7.18 g (40.3 mmol) of 4-morpholinoaniline, dissolved in 60 ml of dioxane, were added dropwise. The mixture was stirred at room temperature for 12 h, and the resulting precipitate was filtered off and dissolved in a dichloromethane/water (1:1) solvent mixture. The organic phase was separated off, dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [N+:1]([CH2:4][C:5](=O)[CH3:6])([O-:3])=[O:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])=[CH:11][N:10]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:5]([CH3:6])=[CH:4][N+:1]([O-:3])=[O:2])=[CH:11][N:10]=1
Reactant: CN(CCN)Cc1ccc(Cl)nc1
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Yield: 70.1 %

Procedure:
Nitroacetone (1.1 g) and N-(2-chloro-5-pyridylmethyl)-N-methylethylenediamine (2.0 g) were dissolved in toluene (60 ml), and the solution was refluxed for 3 hours in a flask equipped with a water separating device while removing water formed by the reaction. Toluene was concentrated under reduced pressure, and the remaining solid was recrystallized from ethanol to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-methyl-2-nitrovinyl)ethylenediamine (2.0 g) having a melting point of 78° to 80° C.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14]([CH:16]([CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])C1C=CC=CC=1.[OH:34]O.O.[OH-].[Li+]>O1CCCC1.O>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH:16]([CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([OH:15])=[O:34])([CH3:24])([CH3:23])[CH3:22]
Reactant: OO
Reactant: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)O
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of tert-butyl 3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-cyclohexylhexanoate (64.0 g, 139.9 mmol) in tetrahydrofuran:water (3:1, 800 ml) was cooled to 5° C. then treated sequentially with hydrogen peroxide (30%w/v water, 87 ml, 769 mmol) then lithium hydroxide hydrate (10.0 g, 238 mmol). The reaction was stirred for 1 hour then quenched by dropwise addition of an aqueous solution of sodium thiosulphate (500 ml) keeping the temperature below 20° C. The mixture was extracted with ethyl acetate (discarded) and the aqueous phase was acidifed to pH 2 with solid citric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (2:1) gradually changing to hexane:ethyl acetate (1:1) to afford the title compound (40.7 g)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:22]#[N:23])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=2[CH:21]=1)([O-])=O.[Cl-].[NH4+].O>C(O)C.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:22]#[N:23])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:19])([CH3:20])[C:13]=2[CH:21]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3[nH]c(C#N)cc3[N+](=O)[O-])cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(-c3[nH]c(C#N)cc3N)cc21
Temperature: 80 °C
Yield: 80.3 %

Procedure:
A solution of 4-nitro -5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (0.4 g, 1.28 mmol) in ethanol/water (5:1, 20 mL) was treated sequentially with zinc powder (2.5 wt, 1.0 g) and ammonium chloride (5 wt, 2.0 g). The suspension was heated at 80° C. or 30 min, cooled to room temperature, poured into water (30 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with ethyl acetate to give 4-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (0.29 g, 80%) as a yellow solid. 1H NMR (500 MHz, d6-DMSO) δ 1.63 (s, 6H), 4.29 (s, 2H), 6.39 (s, 1H), 6.89 (d, 1H, J=8.1 Hz), 7.49 (s, 1H), 7.52 (dd, 1H, J=8.1 and 2.3 Hz), 10.25 (s, 1H), 11.76 (s, 1H). MS (ESI (−)) m/z 281 (M−H)−. Anal. calcd for C15H14N4O2, C, 63.8, H, 5.00, N, 19.9. Found, C, 63.7, H, 5.10, N, 19.82
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23](O)=[O:24])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([Cl:33])=[O:24])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.6 g (1.553 mmol) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)-benzoic acid were suspended in 20 ml of dichloromethane with magnetic stirring, the mixture was placed in a bath at 0° C. and then 0.408 ml (4.66 mmol) of oxalyl chloride were added drop wise, finally a few drops of dimethylformamide were added. The cold bath was withdrawn and then the mixture was stirred at r.t. for 2 h. The reaction medium was concentrated in vacuo and immediately used in the next step.
Reaction SMILES: C([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](COCC)[C:16]([Br:25])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=O)C.Cl>CO.CCOCC>[OH:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([Br:25])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (prepared as described for CT12440) (3.8 g, 8.5 mmol ) in methanol (150 ml) was added a solution of hydrogen chloride in ether (1.0 M, 20 ml). The reaction mixture was stirred at room temperature for 24 hours. Evaporation of the solvent under reduced pressure provided (R)-1-(5-hydroxyhexyl)-8-bromo-3-methylxanthine (2.9 g, 98% yield) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH:46]([CH3:49])[CH2:47]Cl>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:47][CH:46]([CH3:49])[CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(CCl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CC1CS/C(=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)N(c2ccccc2C(C)C)C1
Temperature: 80 °C

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (100 mg, 0.191 mmol) and potassium carbonate (105 mg, 0.763 mmol) in butanone (4 ml) was added 1-bromo-3-chloro-2-methylpropane (39.0 mg, 0.229 mmol). The reaction was heated to 80° C. overnight. The reaction mixture was then diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided the title compound as a light yellow solid as a mixture of rotational diastereoisomers: mp 186-190° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=3.6 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.06 (s, 1H), 7.84-7.77 (m, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.38 (d, J=9.0 Hz, 3H), 7.32 (td, J=7.5, 1.4 Hz, 1H), 7.26 (s, 1H), 7.17 (t, J=7.1 Hz, 1H), 3.69-3.26 (m, 1H), 3.55-3.37 (m, 1H), 3.18-2.98 (m, 2H), 2.93-2.80 (m, 1H), 2.47 (d, J=35.9 Hz, 1H), 1.31-1.12 (m, 9H); ESIMS m/z 580 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH:9](O)[CH3:10])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C([N:34](CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH:9]([NH2:34])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(O)C(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CC(N)C(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
141 mg of the alcohol compound thus obtained was dissolved in 2 ml of ethyl acetate, and 62 μl of methanesulfonyl chloride and 161 μl of triethylamine were added thereto, followed by stirring at room temperature for 30 minutes. Insoluble precipitates were filtered off from the reaction solution. Then, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 5 ml of dimethylformamide. Then, 255 mg of sodium azide was added thereto, followed by heating at 80° C. for 4 hours. The reaction solution was left to cool to room temperature. Then, ethyl ether and water were added thereto for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was heated and refluxed together with 187 mg of triphenylphosphine in 7 ml of 10%-water containing tetrahydrofuran for one hour. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was dissolved in ethanol and again evaporated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=50/1→10/1) to obtain 129 mg (yield: 92%) of (1RS, 2SR)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)propylamine.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[NH4+:12].C(O)C.O>C(O)C>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Reactant: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of 2,6-dibromo-3-nitropyridine (5.00 g) in ethanol (10 ml) was added a solution (6.8 M, 15 ml) of ammonium/ethanol at room temperature, and the mixture was stirred at room temperature for 19 hr in a sealed container. Water (25 ml) was added to the reaction mixture, and the precipitate was collected by filtration and washed with ethanol. This was suspended in ethanol (55 ml), heated, and allowed to cool. The precipitate was collected by filtration to give 2-amino-6-bromo-3-nitropyridine as a yellow powder (3.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH:30]([NH:33][CH2:34][CH2:35]O)([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][NH:33][CH:30]([CH3:32])[CH3:31])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CC(C)NCCO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(1-methylethyl)amino]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(isopropylamino)ethanol following General Procedure K.
Reaction SMILES: CS(C)=O.[C-:5]#[N:6].[Na+].[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](Cl)=[N:16][O:17][CH3:18]>CCOCC>[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](=[N:16][O:17][CH3:18])[C:5]#[N:6]
Reactant: CON=C(Cl)c1ccccc1COc1cc(C)ccc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Dimethyl sulfoxide (2 ml) and 95% sodium cyanide (0.21 g, 0.004 mol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl chloride (0.60 g, 0.002 mol), and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (0.45 g, 76.4%) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH3:37])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([O:33][CH:34]([F:36])[F:35])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[NH2:7][C@H:8]1[C@@H:9]([NH:16][C:17]([C:19]2[S:20][C:21]([CH3:37])=[C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[C:31]([O:33][CH:34]([F:35])[F:36])[CH:30]=[N:29][C:28]=34)[CH:23]=2)=[O:18])[C:10]([F:14])([F:15])[CH2:11][CH2:12][CH2:13]1
Reactant: Cc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
tert-Butyl{(1R,2R)-2-[({4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamate (0.900 g, 1.61 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (1.50 mL, 19.5 mmol) added. The reaction was stirred at room temperature for 16 h. After deprotection was complete, the mixture was diluted with 1N NaOH. The aqueous layer was extracted 3× with dichloromethane. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-16% MeOH/DCM) to give the title compound (0.371 g, 0.811 mmol). LRMS (APCI) calc'd for (C19H19F4N5O2S) [M+H]+, 458.1; found 458.0. 1H NMR (CDCl3, 500 MHz) δ 8.66 (d, J=2.5, 1H), 8.48 (d, J=2.5, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.06 (d, J=8.8, 1H), 6.61 (t, J=71.5, 1H), 4.45 (m, 1H), 3.32 (m, 1H), 2.57 (s, 3H), 2.17 (m, J=8.6, 1H), 1.47-1.92 (m, 5H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:14])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:14][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC#CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC#CCCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
7.47 g (65 mmol) of methanesulfonyl chloride are added dropwise within 30 minutes at 10° C. to a solution of 7.56 g (60 mmol) of 3-octyn-1-ol and 12.45 ml (90mmol) triethylamine in 225 ml of methylene chloride, and the mixture is stirred for one hour. The reaction solution is washed with water, saturated sodium bicarbonate solution and again with water, dried and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1.[CH2:13]=[O:14]>CO.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH2:9][CH2:13][OH:14])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Reactant: C=O
Solvent: CS(C)=O
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(CCO)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.7 %

Procedure:
Triton B (2 ml, 35% in MeOH) was added at 80° C. to a mixture of 5-methoxy-2-nitrotoluene (25 g, 150 mmol) and paraformaldehyde (2.3 g, 73 mmol) in DMSO (20 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After being stirred 2.5 h at this temperature, it was cooled to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with H2O (50 ml) and extracted with EtOAc (5×100 ml). The organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a distillation in a high vacuum (p=0.1 torr), whereby a fraction containing starting material (12.1 g) was obtained at 70° C. The residual crude product was purified by column chromatography (240 g SiO2, solvent: toluene/EtOAc 8:1 1400 ml, 7:1 1600 ml, 6:1 400 ml, 5:1 400 ml, 3:1 400 ml, 2:1 600 ml and 1:1 600 ml). 2-(5-methoxy-2-nitrophenyl)ethanol (6.87 g, 48%) was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].C1([Mg]Br)C=CC=CC=1.[Li]CCCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[OH:8]
Reactant: O=Cc1ccccc1
Reactant: Oc1c(Br)cncc1Br
Agent: Br[Mg]c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Oc1c(Br)cncc1C(O)c1ccccc1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a heterogeneous mixture of 3,5-dibromo-4-hydroxypyridine (2.53 g, 10 mmol, prepared following the procedure in Synthesis, 2001, 14, 2175-2179) in anhydrous THF (20 mL) at −78° C. under Ar-atm was added phenylmagnesium bromide solution (11 mL of 1 M solution in THF, 11 mmol). After stirring for 15 min. was added n-BuLi solution (5.5 mL of 2 M solution in cyclohexane), and the reaction mixture was stirred for 15 min at −78° C. under Ar-atm. To this mixture benzaldehyde (2.15 mL) was added and the reaction mixture was stirred for 2 h −78° C. under Ar-atm. The reaction mixture was quenched by adding HOAc (3 mL) and TFA (3 mL), concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc/MeOH//750:250:50 followed by hexane/EtOAc/MeOH/Et3N//460:460:50:10 to afford the desired product (2.85 g, 91%) as a white solid. 1H NMR (CD3OD) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.41-7.20 (m, 5H), 5.94 (s, 1H); MS(ESI+) m/z 280, 282 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH2:24])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.O=C1CCC(=O)N1[O:39][C:40](=O)[CH:41]=[N+:42]=[N-:43]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10](=[CH2:24])[CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH3:23])[C:40](=[O:39])[CH:41]=[N+:42]=[N-:43])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=CC(=O)ON1C(=O)CCC1=O
Reactant: C=C(CNCc1ccc(OC)cc1OC)CO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C(CO[Si](C)(C)C(C)(C)C)CN(Cc1ccc(OC)cc1OC)C(=O)C=[N+]=[N-]
Reaction time: 16 h
Yield: 48.7 %

Procedure:
To a solution of [2-(tert-butyldimethylsilanyloxymethyl)allyl]-(2,4-dimethoxybenzyl)amine (384 mg) in chloroform (3.8 ml) were sequentially added triethylamine (0.23 ml) and diazoacetic acid 2,5-dioxopyrrolidin-1-yl ester (200 mg) at room temperature, and the mixture was stirred for 16 hours. This reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give the titled compound (223 mg).