Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]=[CH:10][CH3:11])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(C)=O>CN(C=O)C.O>[CH2:14]([O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH:9]=[CH:10][CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC=Cc1ccc(Br)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC=Cc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-2-(propenyl)-phenol (mixture of E- and Z-isomer ca. 85:15) (1.10 g, 4.99 mmol, 1.0 eq.) in DMF (15 mL) was slowly added to sodium hydride 60% dispersion in mineral oil (261 mg, 6.52 mmol, 1.3 eq.) at 0° C. under N2. Upon completion of the addition, the mixture was allowed to warm to r.t. Benzyl bromide (0.61 mL, 4.99 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. AcOEt was added and the reaction was stirred at r.t. for 30 min. Water was added to the mixture. The layers were separated and the org. phase was washed with water and sat. aq. NaCl soln., dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+10% AcOEt) to yield 2-benzyloxy-4-bromo-1-(propenyl)-benzene as a pale yellow oil as an unseparable mixture of E- and Z-isomers (ca. 9/1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH:6]=[CH:7][C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)N>C(O)(=O)C>[Br:20][C:21]1[CH:27]=[C:26]([NH:2][C:1]2[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([NH:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH:4]=3)[N:9]=[CH:10][N:11]=2)[CH:25]=[CH:23][CH:22]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC#CC(=O)Nc1ccc(N=CN(C)C)c(C#N)c1
Solvent: CC(=O)O
Product: CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.25 h

Procedure:
A solution of 3.0 g (11.8 mmol) of N-[3-cyano-4-[[(dimethylamino)methylene]amino]phenyl]-2-butynamide and 2.23 g (12.98 mmol) of 3-bromo aniline in 18 ml of acetic acid was refluxed gently with stirring under nitrogen for 1 hr 15 min.. The mixture was cooled in an ice bath and a solid mass formed. The solid was collected by filtration and washed with ether-acetonitrile 1:1 to give a yellow solid which was recrystallized from ethanol giving 2.51 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide: mass spectrum (m/e): 381, 383.
Reaction SMILES: O.[PH2]([O-])=O.[Na+].C=C.Cl.N(C(C(=N)N)(C)C)=NC(C(=N)N)(C)C.O.O.O.O.O.O.[Cl-].[Al+3:30].[Cl-].[Cl-].[Al+3].[CH2:34]([P:36](CC)(=[O:38])[O-:37])[CH3:35].[CH2:41]([P:43](CC)(=[O:45])[O-:44])[CH3:42].[CH2:48]([P:50](CC)(=[O:52])[O-:51])[CH3:49]>O>[Al+3:30].[CH2:34]([P:36]([O-:38])[O-:37])[CH3:35].[CH2:41]([P:43]([O-:45])[O-:44])[CH3:42].[CH2:48]([P:50]([O-:52])[O-:51])[CH3:49].[Al+3:30]
Reactant: CCP(=O)([O-])CC
Agent: C=C
Agent: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: Cl
Solvent: O
Product: CCP([O-])[O-]
Temperature: 100 °C
Yield: 95.9 %

Procedure:
1500 g (14 mol) of sodium hypophosphite monohydrate are dissolved in 7.5 kg of water and initially charged in a 16 l steel-enamel jacketed pressure reactor. After heating the reaction mixture to 100° C., a reducing valve set to 6 bar is used to introduce ethylene into the reactor up to saturation. While stirring constantly at an ethylene pressure of 6 bar and a temperature of 100-110° C., a solution of 19 g (0.5 mol %) of 2,2′-azobis(2-amidinopropane) hydrochloride in 300 g of water is metered in homogeneously. At a conversion of ethylene of 87.3%, the metered addition of 2,2′-azobis(2-amidinopropane) hydrochloride is stopped and the reactor is decompressed. After cooling to about 90° C., 650 g (4.67 mol of aluminum) of aluminum chloride hexahydrate in 2350 g of water were added within 60 minutes. Subsequently, the resulting solid is filtered off, washed with 2 l of hot water and dried at 130° C. under reduced pressure. The resulting mixture comprises diethylphosphinic acid aluminum(III) salt and ethylphosphonous acid aluminum(III) salt in a ratio of 83.3% by weight of diethylphosphinic acid aluminum(III) salt and 16.7% by weight of ethylphosphonous acid aluminum(III) salt (95.9% yield).
Reaction SMILES: P(O)(O)([O-])=O.[K+].P(O)([O-])([O-])=O.[K+].[K+].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.CCCCCCCCCC.[Br:68][CH2:69][C:70](=[O:78])[CH2:71][C:72]([O:74][CH:75]([CH3:77])[CH3:76])=[O:73]>CC(O)C>[Br:68][CH2:69][CH:70]([OH:78])[CH2:71][C:72]([O:74][CH:75]([CH3:76])[CH3:77])=[O:73]
Reactant: CC(C)OC(=O)CC(=O)CBr
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: CCCCCCCCCC
Solvent: CC(C)O
Product: CC(C)OC(=O)CC(O)CBr
Temperature: 25 °C

Procedure:
To 50 ml of 50 mM monopotassium phosphate-dipotassium phosphate buffer (pH 7.0) containing 5% of 2-propanol were added 0.1 mmol of NAD+ and 6 g of the washed cells described above. To this mixture was added 50 ml of decane containing 70 mg (0.31 mmol) of isopropyl 4-bromo-3-oxobutanoate, and the mixture was stirred at room temperature for a night and day. Celite was then put into the reaction solution, and stirred for a while and filtered off to separate the resultant solution. The aqueous layer was further extracted three times with ethyl acetate, and combined organic layers were concentrated to give 50 mg of isopropyl 4-bromo-3-hydroxybutanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15].S(C1C=CC(C)=CC=1)(O[CH2:22][CH3:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:22][CH3:23])[CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1C[C@@H](C(=O)OC)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C

Procedure:
A mixture of methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate from Preparation 31 (500 mg, 2.07 mmol), ethyl tosylate (519 mg, 2.59 mmol) and potassium carbonate (573 mg, 4.15 mmol) were heated in acetonitrile at 70° C. for 16 hours under nitrogen. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (30 ml) and partitioned with saturated aqueous sodium bicarbonate (30 ml). The organic layer was then washed with brine (20 ml), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The above procedure was performed in duplicate. The crude products from the two reactions were then combined and purified by column chromatography on silica eluting with dichloromethane:methanol (99:1) to give the title compound as a pale yellow oil, 968 mg.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[O:19]([C:17]([NH:2][N:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1)=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN1CC=CCC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CC=CCC1)Oc1ccccc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (2.024 g) in methylene chloride (60 ml) was added a solution of phenyl chloroformate (1.566 g) in methylene chloride (40 ml) and the mixture was stirred for 4 hours at 5° C. Evaporation of the solvent gave a residue, which was extracted with ethyl acetate (150 ml). The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give N-(phenoxycarbonylamino)-1,2,3,6-tetrahydropyridine (2.01 g), which was recrystallized from diisopropyl ether to give the desired compound (0.732 g) as colorless needles.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[OH:20]>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[OH:20])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)NC1CCCCC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of cyclohexyl isocyanate (400 mg, 3.19 mmol) in toluene, 2-amino-5-nitrophenol (492 mg, 3.19 mmol) was added. The reaction mixture was stirred at 80° C. for 24 hours, then cooled to room temperature. The product was purified by precipitation from toluene and filtering (752 mg, 93%). m.p: 1850-186.0° C.; EI-MS m/z 280 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14](O)[CH3:15])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[O:20])[N:9]=2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C[O-].[Na+].Cl>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[CH3:15])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)=[O:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C/C=C/n1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
22 mg (0.047 mmol) of 2-[3-(4-chlorophenyl)-4-(2-hydroxypropyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-(trifluoromethyl)benzyl]-acetamide from Example 454 are dissolved in 1 ml of pyridine and treated at RT with 9.6 mg (0.084 mmol) of methanesulphonyl chloride. This is stirred for 2 hrs at RT. Next, it is diluted with 5 ml ethyl acetate and washed three times with 5 ml of 1 N hydrochloric acid each time. The organic phase is dried over sodium sulphate, filtered and concentrated in vacuo. The residue is dissolved in 1 ml of dry methanol, treated with 20 mg (0.94 mmol) of sodium methanolate, and stirred for 18 hrs at RT. To complete the reaction, a further 81 mg (0.38 mmol) of sodium methanolate are added, and the mixture is further stirred at RT for 48 hrs. The mixture is neutralised with 0.5 ml of 1 N hydrochloric acid and purified directly by preparative HPLC [Method 10]. 4.8 mg (23% of theory) of the target compound are thus obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[CH:21]=[C:20]([O:27][CH:28]([CH3:30])[CH3:29])[C:19]=2[F:31])[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[NH:32]([CH2:36]CO)[CH2:33]CO>CN(C=O)C.CCOC(C)=O>[CH3:33][N:32]([CH3:36])[C:2]1[N:7]=[C:6]([N:8]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[CH:21]=[C:20]([O:27][CH:28]([CH3:30])[CH3:29])[C:19]=2[F:31])[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1cc(CN(c2ccc(C#N)cc2)c2cccc(Br)n2)c(F)c(OC(C)C)c1
Reactant: OCCNCCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2cccc(N(C)C)n2)c(F)c(OC(C)C)c1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A mixture of Intermediate 138.1 (30 mg, 0.124 mmol) and diethanolamine (32.6 mg, 0.31 mmol) in DMF (0.5 mL) was stirred at 130° C. for 5 h, then 140° C. for 15 h. The mixture was diluted with EtOAc, washed with water (2×) and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel, then was concentrated. The crude residue was used in the following step without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:20]=[CH:19][C:18]2[C:14](=[CH:15][N:16]([CH3:21])[N:17]=2)[C:13]=1[CH2:22][OH:23].C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:20]=[CH:19][C:18]2[C:14](=[CH:15][N:16]([CH3:21])[N:17]=2)[C:13]=1[CH:22]=[O:23]
Reactant: Cn1cc2c(CO)c(Cl)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1cc2c(C=O)c(Cl)ccc2n1
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of dimethyl sulfoxide (5.70 mL, 80.0 mmol) in dichloromethane (100 mL) was added oxalyl chloride (3.51 mL, 40.1 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (5-chloro-2-methyl-2H-indazol-4-yl)methanol (2.63 g, 13.4 mmol) in dichloromethane (34 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (16.9 mL, 120 mmol) at −78° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/4) to give the title compound (2.20 g, yield 85%).
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C([C:14]2[CH:67]=[CH:66][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23](C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[CH3:92][N:93]([CH3:97])[CH2:94][CH2:95][OH:96].C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>>[CH2:19]([O:18][C:17]1[CH:16]=[CH:15][C:14]([O:96][CH2:95][CH2:94][N:93]([CH3:97])[CH3:92])=[CH:67][CH:66]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Reactant: CN(C)CCO
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: Oc1ccc(OCc2ccccc2)cc1
Product: CN(C)CCOc1ccc(OCc2ccccc2)cc1

Procedure:
Compound 75A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with 2-(dimethylamino)ethanol and 4-(benzyloxy)phenol, respectively: 1H NMR (DMSO-d6): δ 7.31-7.44 (m, 5H), 6.84-6.94 (m, 4H), 5.03 (s, 2H), 3.94-3.98 (m, 2H), 2.57 (d, J=5.93 Hz, 2H), 2.19 (s, 6H). ESI (+)/MS: 272 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[N:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[N:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2cnc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1cnc(Cn2ncc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [C:1]1([NH:11][C:12]2[CH:13]=[C:14]([C:20]3[N:25]=[C:24](CNC(=O)OC(C)(C)C)[CH:23]=[N:22][CH:21]=3)[CH:15]=[N:16][C:17]=2[O:18]C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[NH+:36]1C=CC=C[CH:37]=1>C([O-])([O-])=O.[Na+].[Na+]>[C:1]1([NH:11][C:12]2[C:17](=[O:18])[NH:16][CH:15]=[C:14]([C:20]3[CH:21]=[N:22][CH:23]=[C:24]([NH:36][CH3:37])[N:25]=3)[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: COc1ncc(-c2cncc(CNC(=O)OC(C)(C)C)n2)cc1Nc1nccc2ccccc12
Reactant: c1cc[nH+]cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNc1cncc(-c2c[nH]c(=O)c(Nc3nccc4ccccc34)c2)n1
Yield: 27 %

Procedure:
tert-butyl 6-(5-(isoquinolin-1-ylamino)-6-methoxypyridin-3-yl)pyrazin-2-ylmethylcarbamate (75 mg, 0.16 mmol, 1 eq.) and pyridinium hydrochloride (378 mg, 3.27 mmol, 20 eq.) were stirred at 150° C. for 10 minutes, allowed to cool to Rt and diluted with sat. Na2CO3 (10 mL). The resulting suspension was sonicated and filtered. The solid collected was washed with water (3×10mL), iso-propanol (1×5mL), diethyl ether (3×10 mL) and pentane (3×10 mL) to give a light brown powder (14.9 mg, 27% Yield).
Reaction SMILES: [C:1]([C:3]([NH:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)([CH3:17])[CH2:4][N:5]1[N:9]=[C:8]2[C:10]([Cl:16])=[CH:11][C:12]([Cl:15])=[C:13]([Cl:14])[C:7]2=[N:6]1)#[N:2].[NH4+]=[S:33]>CO>[CH3:17][C:3]([NH:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:22][CH:21]=1)([C:1](=[S:33])[NH2:2])[CH2:4][N:5]1[N:9]=[C:8]2[C:10]([Cl:16])=[CH:11][C:12]([Cl:15])=[C:13]([Cl:14])[C:7]2=[N:6]1
Reactant: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CO
Product: CC(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)(NC(=O)c1ccc(OC(F)(F)F)cc1)C(N)=S
Yield: 47 %

Procedure:
A solution of N-[1-Cyano-1-methyl-2-(4,5,7-trichloro-2H-benzotriazol-2-yl)-ethyl]-4-trifluoromethoxybenzamide (60 mg, 0.12 mmole, described in U.S. Provisional Application SN: 60/930,485 as compound 1.064) and ammonium sulfide (0.04 mL, 40-48 wt. % in water from Sigma-Aldrich) in methanol (4 mL) was irradiated for 20 minute in a self-tunable CEM microwave Discover synthesizer at 80° C. (initial power 100 Watts) and then cooled using a flow of compressed air, evaporated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate. The organic extracts were combined, washed with brine, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that that was purified by chromatography (SiO2, heptane/ethyl acetate) to afford the title compound as a solid (30 mg, 47%) along with recovered starting material (22 mg, 37%). MS (ES): M/Z [M+H]=526 and [M−H]=524. 1H NMR: (400 MHz, DMSO-d6): 1.48 (s, 3H), 5.59 (d, J=13.3 Hz, 1H), 5.70 (, J=13.3 Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.88 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 8.16 (s, 1H), 9.34 (s, 1H) and 9.83 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.2 (s, 3F).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]2[O:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:32]N1C(=O)CCC1=O>C1COCC1>[Br:32][CH2:2][C:1]([C:4]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]2[O:8][CH2:9][C:10]([CH3:11])([CH3:12])[C:6]=2[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)CBr)cc2c1OCC2(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 5-acetyl-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (2.46 g, 10.0 mmol) in 25 mL of anhydrous THF is added dropwise to lithium diisopropylamide (6.0 mL, 12.0 mmol, 2.0M solution in heptane-THF-ethyl benzene) at -78° C. The resulting solution is stirred at -78° C. for 15 min, and chlorotrimethylsilane (1.5 mL, 12.0 mmol) is introduced. The reaction mixture is stirred at -78° C. for 15 min, warmed to room temperature, stirred for 1.5 h, quenched with water, and extracted with ether. The extract is dried over anhydrous sodium sulfate and concentrated in vacuo; the residue is dissolved in 25 mL of anhydrous THF and reacted at 0° C. with N-bromosuccinimide (1.78 g, 10.0 mmol). The resulting yellowish solution is kept at 0° C. for 0.5 h, warmed to room temperature, stirred for 0.5 h, quenched with water, and extracted with ether. The extract is dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5%→20% ether-hexane) affords about 2.85 g (88%) of 5-bromoacetyl-7-tert-butyl-2,3-dihydro-3,3-dimethyl-benzo[b]furan as a yellowish solid: mp 54-56° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.Cl.[F:18][C:19]([F:25])([F:24])[C:20](=O)[CH2:21][CH3:22]>O1CCCC1>[F:18][C:19]([F:25])([F:24])[C:20]([CH2:21][CH3:22])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCC(=O)C(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(CC)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5.6 g of sodium hydride (60% in oil) in 500 ml of tetrahydrofuran was added dropwise 31.6 g of ethyl diethylphosphonoacetate under ice-cooling. After the mixture was stirred at the same temperature for 10 minutes, the a solution of 1,1,1-trifluoro-2-butanone in diethyl ether obtained in Step 1 was added dropwise thereto. The mixture was stirred at the same temperature for 1 hour, and then warmed to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain crude ethyl 3-trifluoromethyl-2-pentenoate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[CH:6][C:5]3[C:8]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)=[N:9][N:10]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[C:4]=3[CH:3]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1
Reactant: Cn1cc(-c2nn(C3CCCCO3)c3cc(Cl)ncc23)cn1
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2cc3c(cn2)c(-c2cnn(C)c2)nn3C2CCCCO2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.06 g, 0.2 mmol), 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.060 g, 0.23 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (10 mg, 0.02 mmol), and potassium phosphate (80. mg, 0.38 mmol) in 1,4-dioxane (0.5 mL) and water (0.07 mL) in a reaction vial was degassed and sealed. The mixture was stirred at 90° C. for 2 h. After cooling it 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 (80 mg). LCMS (M+H)+=420.2.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCCC#CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC#CCCCC(=O)O
Temperature: 5 °C
Yield: 66.4 %

Procedure:
Hydrazine hydrate (0.1 ml) was added to a solution of 7-phthalimidohept-5-ynoic acid (0.55 g) in ethanol (25 ml). The mixture was refluxed for 3.5 hours and then the solvent was removed under reduced pressure. The residue was suspended in water (20 ml), the pH of the solution was adjusted to 5, and the solid was collected by filtration. The filtrate was evaporated to dryness and the residue was extracted with ethanol (3×5 ml). The ethanol extracts were cooled (5° C.) and the resulting precipitate was collected to give the title compound (0.19 g) m.p. 180°-183° C.