Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.O.CO.C(Cl)Cl>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: CN1CCC[C@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of Intermediate B (179 mg, 1.10 mmol) in dry DMF (2.5 mL) was added NaH (60% in mineral oil, 333 mg, 5.00 mmol) at RT and stirred for 15 min. Intermediate 5b (220 mg, 1.00 mmol) in DMF (2.5 mL) was then added and the mixture heated at 60° C. for 1 h. After cooling, the resulting dark brown mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as light brown powder after freeze drying (224 mg, 61%). LCMS (Method 3): Rt 1.34 min, m/z 364 [MH+].
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][C:7]([Cl:14])=[CH:6][CH:5]=2.Cl>CN(C)C=O>[CH2:10]([O:13][C:2]1[C:3](=[O:15])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[O:15][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][C:7]([Cl:14])=[CH:6][CH:5]=2)[CH2:9][CH2:8][CH3:7]
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2cc(Cl)ccc21
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCOC1=C(OCCCC)C(=O)c2cc(Cl)ccc2C1=O
Yield: 68.2 %

Procedure:
To a solution of sodium-n-butoxide (25.8 g) in dry dimethylformamide (125 ml) was added 2,3,6-trichloro-1,4-naphthoquinone (28 g) in one amount. The mixture was refluxed for 2 hours, then cooled, acidified with 6M hydrochloric acid and evaporated. The residue was chromatographed over silica gel using dichloromethane as eluant to yield 2,3-di-n-butyloxy-6-chloro-1,4-naphthoquinone (12.3 g) as a red oily solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:48][C:43]2=[CH:44][N:45]=[CH:46][CH:47]=[C:42]2[CH:41]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:48][C:43]3=[CH:44][N:45]=[CH:46][CH:47]=[C:42]3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccncc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3ccncc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Yield: 56.3 %

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol), 2-(tributylstannyl)thieno[2,3-c]pyridine (510 mg, 1.202 mmol) and tetrakis(triphenylphosphine)palladium(0) (463 mg, 0.401 mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 5-50% EtOAc and hexane over a period of 120 minutes. The fractions were collected to give the title compound (135 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([NH:1][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1cc2c([nH]c1=O)CCc1ccccc1-2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c([nH]c1=O)CCc1ccccc1-2

Procedure:
To 2.0 gm of 2-amino-5,6-dihydrobenzo[f]quinolin-3(4H)-one, in 100 ml of chloroform containing 1 ml of pyridine add 0.80 gm of acetyl chloride. Stir the reaction at room temperature for 5 hours. Filter and wash the solution with water. Remove the solvent by stripping to give the title compound.
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]2[CH2:41][C@H:40]3[N:42]([CH3:43])[C@H:37]([CH2:38][CH2:39]3)[C@H:36]2[CH:44]=O)=[CH:31][CH:30]=1.O>CCOCC>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]2[CH2:41][C@H:40]3[N:42]([CH3:43])[C@H:37]([CH2:38][CH2:39]3)[C@H:36]2/[CH:44]=[CH:8]/[Cl:7])=[CH:31][CH:30]=1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1[C@H]2CC[C@@H]1[C@@H](C=O)[C@@H](c1ccc(Cl)cc1)C2
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CN1[C@H]2CC[C@@H]1[C@@H](/C=C/Cl)[C@@H](c1ccc(Cl)cc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A solution of butyllithium (0.32 mL, 2.5M in hexane, 0.68 mmol) was added to a stirred solution of chloromethyltriphenylphosphonium chloride (237 mg, 0.68 mmol) in dry EtzO (5 mL) at room temperature under N2 atmosphere. The resulting orange mixture was stirred for 30 min at that temperature, and then crude 3β-(4-chlorophenyl)-2β-formyltropane (60 mg, 0.23 mmol) in dry ether (4 mL) was added dropwise. The mixture was stirred at room temperature for 2 hr, cooled at 0° C., mixed with water (2 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude product was purified by flash column chromatography on silica gel saturated with NH3 eluting with hexane:ethyl acetate=1:1. Removal of the solvent gave 2d (14 mg, 20%); [α]D22 =-124° (c=0.52, CHCl3); IR (thin film) 3061, 2930, 2798, 1618, 1492, 941, 925 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 7.23 (d, 2H, J=8.5 Hz), 7 (d, 2H, J=8.5 Hz), 6.14 (dd, 1H, J=13.4, 10 Hz), 5.47 (d, 1H, J=13.4 Hz), 3.27 (s, 1H), 3.03 (m, 2H), 2.28 (m, 1H), 2.22 (s, 3H), 2.18-1.64 (m, 6H); 13C NMR (CDCl3, 75.46 MHz) 141.14, 133.88, 131.75, 129.34, 128.17, 117.55, 67.29, 61.99, 49.64, 41.96, 36.61, 34.50, 26.44, 24.98; mass spectrum, m/z 297 (M+, 37Cl), 195 (M+, 35Cl), 260, 218, 141, 97, 82.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([Cl:26])=[C:19]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:26][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:25])[C:22](=[O:24])[CH3:23]
Reactant: N#Cc1cn[nH]c1N
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)cnn23)ccc1Cl
Yield: 77.1 %

Procedure:
A mixture of 0.046 g (0.43 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.120 g (0.43 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 108 mg of N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 77%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: C1COCCN1
Product: CN(C(=O)c1cc2c(s1)-c1cc(N3CCOCC3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and morpholine were reacted to give 129bp. 1H NMR (400 MHz, CDCl3) δ: 7.27 (m, 1H), 7.11-7.14 (m, 2H), 6.90-6.98 (m, 3H), 6.75 (s, 1H), 5.09 (s, 2H), 4.04 (m, 2H), 3.38 (s, 3H), 3.32 (m, 2H). LCMS (ESI) m/z: 442.9
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(F)(F)F)n1
Yield: 82 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-6-(trifluoromethyl)pyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 135 mg, 82%) which was obtained as a light yellow solid. MS: m/e=329.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17].CC1[C:24](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23](OC)[C:22](OC)=C(OC)C=1OC>>[CH3:1][C:2]1[C:7](/[CH:8]=[C:26](\[CH2:25][CH2:24][CH2:23][CH3:22])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: CCOC(=O)/C=C/c1c(C)c(OC)c(OC)c(OC)c1OC
Product: CCCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)OCC

Procedure:
Compound 8e was prepared from 7 (0.650 g, 2.71 mmol) as described above for 8a to give 0.484 g (1.32 mmol, 49%) of the product as a yellow oil following flash chromatography (1:9 EtOAc:hexanes).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:8][C:7]([O:16]CC1C=CC3C(=CC=CC=3)N=1)=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CS(C)=O.O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][O:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]([CH3:1])=[C:10]2[CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH3:45]
Reactant: Cc1c(CC(=O)NN)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Reaction time: 4 h
Yield: 68.5 %

Procedure:
A solution of 310 mg (1 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide (Example 62) in 25 mL of DMSO was treated with 45 mg (1.1 mmol) of 60% NaH/mineral oil and after 0.25 hours, 0.16 mL (1.1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 4 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with CH2Cl2 →4% MeOH/CH2C2, to give 290 mg (68% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (0.685 mmol) and 2 mL of 2N NaOH in 25 mL of EtOH and 5 mL of THF was stirred for 22.5 hours. The mixture was diluted with water, made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (Na2SO4), and concentrated at reduced pressure. The residue was dissolved in EtOH and precipitated with ether to give 50 mg (47% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid, mp, 160° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[S:9])[S:5][C:6]=1[CH3:7].S(Cl)(Cl)=O.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:15])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: CO
Reactant: Cc1sc(C(O)=S)cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=S)c1cc(Br)c(C)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
To a stirred solution of 4-bromo-5-methylthiothiophene-2-carboxylic acid (87 mmol), prepared according to the procedure of Kleemann, et al., EP 0676395A2, in dry methanol (750 mL) was added thionyl chloride (7 mL, 96 mmol) dropwise. After stirring for 10 min at room temperature, the solution was heated to reflux and stirred 7.5 h. The solution was cooled and the solvents were removed in vacuo. The resulting solid was dissolved in dichloromethane (1500 mL) and washed with saturated sodium bicarbonate (2×300 mL), water (300 mL), saturated brine (300 mL), and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The resulting solid was recrystallized twice from hexane/ethyl acetate to give methyl 4-bromo-5-methylthiothiophene-2-carboxylate (4.4 g, 19%). 1H-NMR (CDCl3, 400 MHz) δ7.66 (s, 1H), 3.90 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH:10]=[C:9]([Br:11])[CH:8]=[N:7]2)[CH2:3]1.[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl>[Br:11][C:9]1[CH:8]=[N:7][N:6]([CH:4]2[CH2:5][N:2]([C:12](=[O:14])[CH3:13])[CH2:3]2)[CH:10]=1
Reactant: Brc1cnn(C2CNC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CC(n2cc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To 1-Azetidin-3-yl-4-bromo-1H-pyrazole hydrochloride (0.3 g, 1.26 mmol) in CH2Cl2 (15 ml) added ET3N (0.47 ml) and acetyl chloride (0.107 ml, 1.5 mmol) stirred at RT for 2 hours then partitioned between EtOAc and H2O. The organic layer was separated, washed with water H2O, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (276 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][OH:14])=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Fc1cccc(-n2cncn2)c1
Product: OCc1ncnn1-c1cccc(F)c1
Temperature: 150 °C

Procedure:
A mixture of the crude 1-(3-Fluorophenyl)-1,2,4-triazole and formaldehyde (10 mL of 37 wt % in water) is heated at 150° C. in a sealed tube for 48 h. After cooling the reaction vessel, the reaction mixture is extracted with dichloromethane, dried (MgSO4), concentrated, and the residue purified using silica gel chromatography to afford 1-(3-Fluorophenyl)-5-hydroxymethyl-1,2,4-triazole. 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.42-7.53 (m, 3H), 7.22-7.29 (m, 1H), 4.81 (s, 2H). LCMS 194.2 (MH−).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[NH:12])[S:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([O:22][C:23]([NH:12][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][CH3:11])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSC(=NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Yield: 92.4 %

Procedure:
N-(tert-butyloxycarbonyl)-S-methylisothiourea (2 g) was dissolved in dichloromethane (20 ml). To the solution, a 4N sodium hydroxide solution (2 ml) was added with stirring. The reaction mixture was placed in an ice bath; N-(benzyloxy-carbonyloxy)-succinimid (2.62 g) in dichloromethane (20 ml) was added dropwise together with a 2N sodium hydroxide solution to keep the pH around 11. After addition was complete, the reaction mixture was stirred overnight at room temperature. The dichloromethane layer was separated, and the aqueous layer was washed twice with dichloromethane. The combined organic layers were washed with water and dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica (eluent: heptane/ethyl acetate=3/2 v/v %) to yield N-(benzyloxy-carbonyl)-N'-(tert-butyloxycarbonyl)-S-methylisothiourea (3.15 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[N:1]([C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)=[C:20]=[O:22]
Reactant: COC(=O)c1ccc(N)nn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N=C=O)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of methyl 6-aminopyridazine-3-carboxylate (14 g, 91.5 mmol) in anhydrous toluene (700 mL) was added Et3N (11.1, 109.8 mmol). A solution of triphosgene (27.2 g, 91.5 mmol) in anhydrous toluene was added slowly at 0° C. The reaction mixture was stirred for 2 hrs at room temperature and then heated at 90° C. for 5 hrs. After cooling to room temperature, toluene and water were added to the mixture, the mixture was separated and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:23]([CH3:22])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CNc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
4-Chloro-3-nitrobenzene-1-sulfonyl chloride (10.6 g, 0.041 mol) was dissolved in toluene (50 ml); and triethylamine (4.14 g, 0.041 mol) was then added. To the resulting solution, N-methylaniline (4.4 g, 0.041 mol) was added under stirring. The reaction mixture was incubated at 70-80° C. for 1 h. Thereafter, it was allowed to cool. The cooled solution was washed twice with 30 ml of water and concentrated under vacuum. The residue was recrystallized from ethanol. The yield of 4-chloro-N-methyl-3-nitro-N-phenylbenzene sulfonamide was 9.4 g (61%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([O:10][CH3:11])(=[O:9])[C:6]([CH3:8])=[CH2:7]>CO>[CH3:11][O:10][C:5](=[O:9])[CH:6]([CH3:8])[CH2:7][NH:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: C=CCN
Solvent: CO
Product: C=CCNCC(C)C(=O)OC
Yield: 78.1 %

Procedure:
A solution of 11.42 g (0.20 mole) of allylamine, 24.03 g (0.24 mole) of methyl methacrylate and 100 mL of methanol in a pressure bottle, was heated at 90 degrees for 43 hours. After cooling the mixture was concentrated, then vacuum distilled under vaccuum to give 24.55 g (rac)-2-methyl-3-(2-propenylamino)-propanoic acid methyl ester as colorless oil. b.p. 70 degrees, 5 mm Hg.
Reaction SMILES: Br[C:2]([F:33])([F:32])[C:3](F)([F:30])[O:4][C:5]1[CH:29]=[CH:28][CH:27]=[C:7]2[C:8]([N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20](F)([F:25])[C:21]([F:24])([F:23])Br)=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=12)=[O:9].BrC(F)(F)C(F)(F)OC1C=CC(N)=CC=1.BrC(F)(F)C(F)(F)OC1C=CC=C2C(OC(=O)C=12)=O.C1(C)C=CC=C(C)C=1>CN1CCCC1=O>[F:30][C:3]([O:4][C:5]1[CH:29]=[CH:28][CH:27]=[C:7]2[C:8]([N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:25])=[C:21]([F:23])[F:24])=[CH:17][CH:18]=3)[C:11](=[O:12])[C:6]=12)=[O:9])=[C:2]([F:33])[F:32]
Reactant: O=C1c2cccc(OC(F)(F)C(F)(F)Br)c2C(=O)N1c1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: Nc1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: O=C1OC(=O)c2c(OC(F)(F)C(F)(F)Br)cccc21
Solvent: CN1CCCC1=O
Solvent: Cc1cccc(C)c1
Product: O=C1c2cccc(OC(F)=C(F)F)c2C(=O)N1c1ccc(OC(F)=C(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
3-(2-Bromotetrafluoroethoxy)-N-(4-(2-bromotetrafluoroethoxy)phenyl)phthalimide Into a 250 ml round bottomed flask fitted with a mechanical stirrer and a Dean-Stark trap is placed 4-(2-bromotetrafluoroethoxy)aniline (3.4 g, 0.0118 mole) in 40 ml of N-methylpyrrolidinone (NMP). In a separate flask, 3-(2-bromotetrafluoroethoxy)phthalic anhydride (3.0 g, 0.00874 mole) is dissolved in 20 ml of NMP and is added slowly drop wise over 15 minutes to the stirring solution of 4-(2-bromotetrafluoroethoxy)aniline in NMP. The mixture is stirred for 30 minutes at room temperature, after which m-xylene (6 ml) is added and the suspension is heated to 40° C. After heating at 40° C. for 1 hour the is heated to reflux (181° C.) and is refluxed for 6.5 hours to remove water azeotropically. Upon cooling the solvent is removed by evaporation under vacuum and the solid precipitate is recrystallized from dichloromethane/hexane solution (2:1) to provide the product as a light yellow crystalline solid (4.37 g, 81.5 percent yield) with a melting point of 172°-172.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C(N(CC)CC)C.Cl[S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20].Cl>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(OS(=O)(=O)c2nc[nH]n2)c(C)c1

Procedure:
4.1 g of 2,4,6-trimethylphenol was dissolved in 15 ml of dichloromethane, and 4.2 ml of triethylamine was added while stirring the solution. Further, 4.6 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while being cooled with ice and stirred. Then, the solution was stirred at room temperature for 14 hours. After that, 2N hydrochloric acid was added to separate the components. The organic layer was washed with water, and then it was dried with magnesium sulfate. Then, the solvent was removed by distillation, so that coarse crystals were obtained. The coarse crystals were recrystallized from n-hexane/ethyl acetate, so that 3.0 g of the titled compound was obtained.