Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O.[NH2:15][NH2:16]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:15][NH2:16])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NN
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc2[nH]ncc2c1
Yield: 93.4 %

Procedure:
A solution of methyl 1H-indazole-5-carboxylate (5.02 g, 28.5 mmol) and hydrazine monohydrate (6.94 mL, 143 mmol) in methanol (50 mL) was heated under reflux for 48 hr. After cooling, the precipitate was collected by filtration, and washed with methanol to give the title compound (4.69 g, yield 93%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[CH:9]=[C:8]([CH3:10])[S:7][C:6]=2[C:11]=1[Cl:12].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC(=O)CC.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:13][C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[C:6]2[S:7][C:8]([CH3:10])=[CH:9][C:5]=2[CH:4]=1)[CH3:20]
Reactant: Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C)sc2c(Cl)c1Cl
Yield: 93.9 %

Procedure:
A mixture of 2.1 g of 6,7-dichloro-5-hydroxy 2-methylbenzo[b]thiophene, 1.88 g of ethyl bromoacetate, 20 ml of 2-butanone, 2 ml of dimethylformamide and 4.0 g of sodium bicarbonate is refluxed for 16 hours. The cooled mixture is diluted with ice, extracted 3 times with ether and the ether solution is washed, dried and concentrated. The crude oil after removal of solvent is purified by passing it through an alumina column. Elution with ether gives 2.7 g of ethyl[(6,7-dichloro-2-methylbenzo[b]thien-5-yl)oxy]acetate as off-white crystals, mp 91°-92°. An analytical sample is recrystallized twice from hexane and dried at 80°.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].Br[C:16]1[CH:21]=[C:20]([CH:22]=[CH:23][C:24]2[S:25][CH:26]=[C:27]3[O:32][CH2:31][CH2:30][O:29][C:28]=23)[CH:19]=[CH:18][N:17]=1>C1(C)C=CC=CC=1.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>[CH2:30]1[CH2:31][O:32][C:27]2[C:28](=[C:24]([CH:23]=[CH:22][C:20]3[CH:21]=[CH:16][N:17]=[C:18]([C:3]4[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][N:12]=4)[CH:19]=3)[S:25][CH:26]=2)[O:29]1
Reactant: Brc1cc(C=Cc2scc3c2OCCO3)ccn1
Reactant: COC(=O)c1ccnc([Sn](C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2cc(C=Cc3scc4c3OCCO4)ccn2)c1
Yield: 53.4 %

Procedure:
A solution of (12) (95 mg, 0.32 mmol) in toluene (5 mL) was added to a solution of (10) (105 mg, 0.32 mmol) in the same solvent (5 mL). Tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) was added and the resulting mixture was refluxed for 20 min. A brown precipitate was obtained which was collected upon filtration, extensively washed with toluene, and dried under vacuum, yielding the product (8) (65 mg, 53%) which was directly used without further purification in the next step. 1H NMR (500 MHz, CDCl3) δ 8.98 (s, 1H), 8.88 (d, J=4.9 Hz, 1H), 8.65 (d, J=5.1 Hz, 1H), 8.48 (s, 1H), 7.90 (d, J=4.2 Hz, 1H), 7.48 (d, J=16.1 Hz, 1H), 7.37 (d, J=4.4 Hz, 1H), 6.93 (d, J=16.2 Hz, 1H), 6.35 (s, 1H), 4.36-4.34 (m, 2H), 4.28-4.26 (m, 2H), 4.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:14]([NH2:18])(=[O:17])[CH:15]=[CH2:16]>C(O)(=O)C.C(Cl)(Cl)Cl>[NH2:18][C:14](=[O:17])[CH2:15][CH2:16][N:10]1[CH2:9][CH2:8][N:7]([C:5]([O:4][C:2]([CH3:13])([CH3:1])[CH3:3])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC(N)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CCC(N)=O)CC1

Procedure:
A molten mixture of 7.5 (0.04 mole) of 1-(1,1-dimethylethoxycarbonyl)piperazine, 2.9 g (0.04 mole) of acrylamide and 3 drops of acetic acid was stirred and heated at 65° for 18 hours. The mixture which had solidified during the heating period was dissolved in 100 ml of chloroform and washed with dilute aqueous sodium hydroxide solution. The dried (MgSO4) CHCl3 solution was filtered and evaporated in vacuo to yield a white solid. Recrystallization from toluene-hexane returned 8.0 g (78%) of product, m.p. 96°-8°. Calc. for C12H13N3O3 (257.335): C, 56.01; H, 9.01; N, 16.33. Found: C, 56.05; H, 9.04; N, 16.05.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4](=[O:12])[C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:8]([C:5]1[C:4](=[O:12])[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[C:2]([CH3:1])=[CH:7][N:6]=1)=[O:9]
Reactant: COC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CN
Product: CNC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.11 g, 0.35 mmol) was dissolved in a solution of methylamine (33% in ethanol, 5 ml) a vial. The vial was sealed and heated with stirring at 50° C. for 30 minutes. The volatiles were removed in vacuo giving a crude product which was purified for analytical purposes on preparative HPLC to give 0.079 g (73%) of N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:9][C:3]2[C:2]([Br:1])=[N:7][C:6]([CH3:8])=[CH:5][N:4]=2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: Cc1cnc(N)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(Br)n1

Procedure:
Prepared by the method of Example 1 using 3-bromo-5-methyl-2-pyrazinamine and 5-chloro-2-thienylsulphonyl chloride
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])[CH:3]=1
Reactant: CC1(C)CC(=O)c2c(Br)c[nH]c2C1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(=O)c2c(Br)cn(-c3ccccc3C#N)c2C1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-4-one (670 mg, 2.77 mmol), 2-fluorobenzonitrile (0.3 mL, 2.77mmol) and K2CO3 (957 mg, 6.9 mmol) in DMSO (10 mL) was stirred at 100° C. for 3 h. The mixture was cooled to room temperature, poured into water and extracted into EtOAc (3×). The combined organic layers were washed with water (2×), dried (MgSO4) and evaporated. The title compound (858 mg, 91%) was isolated as a beige solid and used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.10 (6H,s), 2.42 (2H,s), 2.51 (2H,s), 6.83 (1H,s), 7.42 (1H,dd, J=7.9 and 0.9Hz), 7.64 (1H,dd, J=7.7 and 1.1 Hz), 7.78 (1H,dd, J=7.9 and 1.5 Hz), 7.85 (1H,dd, J=7.7 and 1.4 Hz). MS (ES+) 343/345 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[C:11]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[C:36]([Br:43])[C:12]=1[CH2:13][N:14]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34]C)=[CH:29][CH:28]=1)[C:15]([NH:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])=[O:16]>CN(C=O)C.[Cu]I>[Br:43][C:36]1[CH:37]=[C:38]([N+:40]([O-:42])=[O:41])[CH:39]=[C:11]2[C:12]=1[CH2:13][N:14]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C:15](=[O:16])[N:17]2[C:18]1[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CCOc1ccc(CN(Cc2c(Br)cc([N+](=O)[O-])cc2Br)C(=O)Nc2c(Cl)cccc2Cl)cc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Br)cc([N+](=O)[O-])cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 130 °C

Procedure:
Diisopropylethylamine (1.78 g, 13.8 mmol) and CuI (2.63 g, 13.8 mmol) was added to N-(2,6-dibromo-4-nitrobenzyl)-N′-(2,6-dichlorophenyl)-N-(4-ethoxybenzyl)urea (4.25 g, 6.88 mmol) in DMF (150 mL). After evacuating and flushing three times with argon, the reaction mixture was heated to 130° C. for 3 h, cooled to rt, and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography on Biotage 40M columns, eluting with 80:20 hexanes-acetone to yield 5-bromo-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-nitro-3,4-dihydroquinazolin-2(1H)-one. Mass spectrum (ESI) 536.0 (M+1).
Reaction SMILES: [N:1]([C@H:4]([CH3:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[N+]=[N-].[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21]>C(O)C.[Pt]=O>[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21].[F:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C@H:4]([NH2:1])[CH3:16])[CH:7]=[CH:8]2
Reactant: C[C@H](Cn1ccc2cc(F)ccc21)N=[N+]=[N-]
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: C[C@@H](N)Cn1ccc2cc(F)ccc21
Yield: 87.7 %

Procedure:
A suspension of 0.1 g of platinum oxide in 25 ml of ethanol was stirred under a hydrogen atmosphere for half an hour and subsequently treated with a solution of 0.92 g of (R)-1-(2-azido-propyl)-5-fluoroindole in 25 ml of ethanol. The reaction mixture was stirred at room temperature for two hours. The catalyst was filtered off and washed with ethanol. The solution was evaporated and the residue was dissolved in 150 ml of ether and treated with 0.58 g (5 mmol) of fumaric acid and stirred overnight. The separated crystals were filtered off and dried. There were obtained 1.14 g (88%) of (R)-2-(5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate (1:1) as white crystals with m.p. 159°-161° (dec.)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[I:42]I>C1COCC1>[I:42][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7]1[N:8]=[N:9][N:10]([C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:11]=1
Reactant: c1ccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Ic1ccccc1-c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 0.5 g (1.3 mmoles) of 18a in 10 mL dry THF cooled to -20° C. under a nitrogen atmosphere was added dropwise with stirring 0.55 mL of 2.5M n-butyl lithium in hexane (1.4 mmoles). When addition was complete, the reaction was allowed to warm to -10° C. over one hour, held there one hour, then cooled to -78° C. After stirring a few minutes, 0.4 g (1.57 mmole) of I2 was added all at once, and stirring continued. After 1 hour the reaction mixture was allowed to warm to ambient temperature. After removal of the solvent, the residue was partitioned between CHCl3 and 1M KH2PO4. The aqueous phase was extracted two more times, the combined organic phases washed with sufficient aqueous Na2S2O3 to remove excess I2, dried (MgSO4) and the solvent evaporated. The residue was crystallized from CH2Cl2 /ether to give 0.3 g product,
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][O:22][CH3:23])[C:18]([NH2:20])=[O:19])=[C:5]([F:24])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:24])=[CH:4][C:3]([C:1]([NH2:2])=[O:31])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][O:22][CH3:23]
Reactant: CC(=O)O
Reactant: COC[C@@H](Nc1cc(Nc2cc(C)ns2)c(C#N)cc1F)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: COC[C@@H](Nc1cc(Nc2cc(C)ns2)c(C(N)=O)cc1F)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-methoxypropanamide (10 mg, 0.028 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (9 mg). MS 368.2 (M+H); UV 219.3, 282.9, 302.6 nm.
Reaction SMILES: [Li]CCCC.[O:6]1[C:10]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:21])[O:19][CH3:20])[CH:14]=[CH:15][CH:16]=2)=[CH:9][N:8]=[CH:7]1.[Cl:22]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:22][C:7]1[O:6][C:10]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:21])[O:19][CH3:20])[CH:14]=[CH:15][CH:16]=2)=[CH:9][N:8]=1
Reactant: COC(=O)Nc1cccc(-c2cnco2)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(-c2cnc(Cl)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
1.6 M nBuLi (9.60 mL, 15.35 mmol) was added dropwise to −78° C. solution of methyl 3-(oxazol-5-yl)phenylcarbamate (1.34 gm, 6.14 mmol) in THF (50 mL). Upon addition the reaction mixture turned red in color. After 60 min, a solution of hexachloroethane (2.18 gm, 9.21 mmol) in THF (10 mL) was slowly added. The reaction was slowly warmed to rt over 30 min. After 2 h at rt the reaction was quenched by slow addition of sat. NH4Cl (20 mL). The mixture was concentrated to remove most of the THF. The mixture was then partitioned between EtOAc (80 mL) and water (30 mL). The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, Methyl 3-(2-chlorooxazol-5-yl)phenylcarbamate, (1.20 gm, 4.75 mmol, 77% yield) as a light yeloow solid. Anal. Calcd. for C11H9ClN2O3 m/z 252.0, found: 253.0 (M+H)+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH2:17][CH:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:12]([CH3:25])[CH:11]=1.N1C=CN=C1>ClCCl.CCOC(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH2:17][CH:18]([O:24][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:14]([CH3:16])[CH:15]=1
Reactant: COC(=O)CC(O)Cc1c(C)cc(Br)cc1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CC(Cc1c(C)cc(Br)cc1C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
TBS-Cl (1291 mg, 4.28 mmol) was added to a solution of 2A (860 mg, 2.86 mmol) and imidazole (389 mg, 5.71 mmol) in dichloromethane (20 mL) and stirred overnight at rt. The reaction was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% ethyl acetate in hexane over 15 min using a 40 g silica gel cartridge) to yield 2B (830 mg, 1.998 mmol, 70.0% yield) as a clear oil. 1H NMR (500 MHz, chloroform-d) δ ppm 7.15 (2H, s), 4.28-4.36 (1H, m), 3.68 (3H, s), 2.82 (2H, ddd, J=53.09, 13.89, 7.02 Hz), 2.53 (2H, ddd, J=57.43, 15.06, 6.19 Hz), 2.33 (6H, s), 0.80 (9H, s), −0.10 (3H, s), −0.32 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:7]#[N:8])([O-:3])=[O:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[N:16]=[N:17][NH:18][N:8]=2)[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2nn[nH]n2)cc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)benzonitrile (400 mg, 1.851 mmol) in DMF (20 mL) was added sodium azide (361 mg, 5.55 mmol) at rt. The mixture was stirred at 120° C. overnight. LCMS showed the reaction was finished. The reaction was quenched by water. The mixture was extracted with EA (20 mL×3), washed with water, and concentrated to give 5-(3-nitro-5-(trifluoromethyl)phenyl)-2H-tetrazole (220 mg, 0.743 mmol, 40.1% yield): 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 7.92 (s, 1H). ES-LCMS m/z 260 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][C:20]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[S:22][N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][CH:28]4[CH2:27][CH2:26][N:25]([C:23]5[S:22][N:21]=[C:20]([CH3:19])[N:24]=5)[CH2:30][CH2:29]4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc2c(-c3ccc(F)c(Cl)c3)cccn2n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(F)c(Cl)c5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h, starting from 8-(3-Chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one. The title compound was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:34]=[CH:33][C:25]2[O:26][C:27]([CH3:32])([CH3:31])[O:28][C:29](=[O:30])[C:24]=2[CH:23]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:34]=[CH:33][C:25]4[O:26][C:27]([CH3:31])([CH3:32])[O:28][C:29](=[O:30])[C:24]=4[CH:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-[(4-butylphenyl)-ethynyl]benzaldehyde and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (purification by flash chromatography on SiO2, EtOAc/c-Hex 15/85) as a yellowish solid (53%). 1H NMR (CDCl3) δ: 7.45 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.15-7.06 (m, 3H), 6.80-6.70 (m, 2H), 4.20 (s, 2H), 4.04 (brs, 1H), 2.57 (t, J=7.7 Hz, 2H), 1.65 (s, 6H), 1.61-1.49 (m, 2H), 1.37-1.23 (m, 2H), 0.88 (t, J=7.3 Hz, 3H). HPLC, Rt: 6.3 min (purity: 92.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26]Br>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[N:8]2[CH2:26][CH2:25][O:24][CH3:23])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Reactant: COCCBr
Product: COCCn1c(C)c(Sc2cccc(CC(=O)O)c2)c2ccc(Cl)cc21

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and 2-bromethyl methyl ether.
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])[CH2:11][CH2:10]1)=O)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1([C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CNC(=O)C1(NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)CNC(=O)C1(N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To 680 mg of compound 22 were added 10 ml of trifluoroacetic acid and 0.5 g of anisole. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. To the residue was added aqueous potassium carbonate and pH was adjusted over 10. The mixture was saturated with sodium chloride and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The procedure gave 410 mg of compound 23.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC.ClCCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([C:15]1[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2F)cc1
Temperature: 0 °C
Yield: 80.6 %

Procedure:
Combine 2,4-difluorobenzoyl chloride (227.8 g, 1.29 mol), anisole (154.2 mL, 1.42 mol) and 1,2-dichloroethane (2.28 L) and cool (−3° C.) under a nitrogen atomosphere. Add aluminum chloride (209.8 g, 1.57 mol) over 45 minutes. The solution color turns from clear to yellow. Pour the reaction mixture over a mixture of ice (1700 g) and concentrated HCl (640 mL) over 2 minutes. The color of the mixture turns from yellow to clear. Separate layers and wash organic layer with 10% potassium carbonate (1600 mL), water (1600 mL), dry (MgSO4), filter and concentrate to give a solid. Stir the solid in heptane (960 mL) and filter to give the title compound as a white solid (258.1 g, 81% Yield): 1H NMR (CDCl3, 200 MHz) δ 3.9 (s, 3H), 6.95 (m, 4H), 7.55 (quar, 1H), 7.8 (d, 2H). Purity by LC/MS (APCl)=100% area, [M+H]+=248 m/e.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[Cl:12][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccnc(CO)c1
Solvent: c1ccccc1
Product: Cc1ccnc(CCl)c1
Reaction time: 8 h

Procedure:
A mixture of 2-hydroxymethyl-4-methylpyridine (5.48 g, 44.5 mmol) and thionyl chloride (60 mL, 822 mmol) in benzene (150 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to provide the title compound as oil. This alkylating reagent was passed through a small plug of activated basic alumina immediately before use.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[CH3:39][NH:40][CH2:41][CH2:42][OH:43]>>[OH:43][CH2:42][CH2:41][N:40]([CH3:39])[CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1
Reactant: CNCCO
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN(C)CCO)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 2-methylaminoethanol were converted to the title compound.