Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[NH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>O1CCCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:40]([N:39]([CH3:43])[CH3:38])=[O:41])[CH:17]=2)[NH:12][C:11]=1[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCNC(=O)OC(C)(C)C)c1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Finely divided {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester (265 mg) was suspended in dry tetrahydrofuran (5mL) and diisopropylethylamine (0.146 mL) and dimethylcarbamoyl chloride (0.077 mL) were added. The reaction mixture was stirred at room temperature for 2.5 days. The reaction mixture was concentrated on a rotary evaporator and the residues were applied to four (20×20 cm 1000μ) preparative silica gel plates and eluted with a solvent system comprising methanol and methylene chloride in the ratio (1:9 v/v). The product (299 mg) was isolated as a thick gum that solidified on prolonged standing.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].ClC1C=CC(S(O)=O)=CC=1C(O)=O.N1C[CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:12]2[CH2:30][CH2:31][O:32][CH2:33][CH2:13]2)(=[O:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: C1COCCN1
Agent: O=C(O)c1cc(S(=O)O)ccc1Cl
Product: O=C(O)c1cc(S(=O)(=O)N2CCOCC2)ccc1Cl
Yield: 100 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and morpholine and obtained in 100% yield. MS (m/e): 304.0 (MH−, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[S:26]1[CH:27]=[CH:28][C:24]([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])=[CH:25]1
Reactant: C#Cc1ccsc1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1C#Cc1ccsc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 3-ethynyl-thiophene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (48 mg, 40%); 1H NMR δ (CDCl3): 8.39 (d, J=8.51 Hz, 1H), 7.9 (br s, 1H), 7.36-7.30 (m, 2H), 7.30-7.21 (m, 3H), 7.02 (t, J=7.24 Hz, 1H), 2.21 (s, 3H); LCMS m/z: 241.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH2:7][CH2:8][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)c1ccc(I)cc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4-Iodoaniline (15.05 g, 6.87×10−2 mol), K2CO3 (19.00 g, 0.137 mol), 1-iodohexane (32.0 ml, 0.217 mol) and dry DMF (170 ml) were added to a 500-ml two-neck round-bottom flask. Ar was bubbled into the reaction mixture for 10 min. The reaction mixture was stirred at 90° C. for 16 h and at 100° C. for 2.5 h under Ar. After cooling, the reaction mixture was filtered to remove inorganic solids. Solvents were removed in vacuo, and water was added to the reaction mixture. The organic layers were extracted with CHCl3, washed with aq. NaHCO3 and water, and dried over Na2SO4. The residue was chromatographed on silica gel 4:1 hexane:CHCl3 as the eluent. Yield=20.47 g (77% based on 15.05 g of 4-iodoaniline). 1H NMR (250 MHz, CDCl3): δ 7.41 (d, 2H, J=8.8 Hz, Ph), 6.40 (d, 2H, J=9.1 Hz, Ph), 3.20 (t, 4H, J=7.6 Hz, —NCH2—), 1.43-1.61 (m, 4H, —NCH2CH2—), 1.18-1.37 (m, 12H, —CH2—), 0.89 (t, 6H, J=6.5 Hz, —CH3). CI MS m/z: 388.149 ((M+H)+) (calcd 388.150).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.CON(C)[C:24]([C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:25]>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:17]([F:20])=[N:18][CH:19]=1
Reactant: COc1cccnc1C(=O)N(C)OC
Reactant: Fc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccnc1C(=O)c1cc(Br)cnc1F
Temperature: -20 °C
Yield: 63.1 %

Procedure:
Diisopropylamine (0.50 ml, 3.54 mmol) and tetrahyrofuran (40 ml) were combined and cooled to −20° C. with stirring. n-Butyl lithium (1.41 ml, 2.5 M in hexanes, 3.53 mmol) was slowly added and stirred at this temperature for 30 minutes. The temperature was decreased to −78 C and neat 5-bromo-2-fluoropyridine (0.38 ml, 3.69 mmol) was added (internal temperature was not allowed to exceed −68 C). The reaction mixture was stirred at −78° C. for 40 minutes. The reaction mixture was added to a solution of 3-methoxy-pyridine-2-carboxylic acid methoxy-methyl-amide (685 mg 3.49 mmol) in tetrahydrofuran (10 ml). This was stirred at −78 C for 1 hour. The reaction mixture was slowly warmed to room temperature, and quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate in hexanes) to give 685 mg (63%) of (5-bromo-2-fluoro-pyridin-3-yl)-(3-methoxy-pyridin-2-yl)-methanone. MS: m/z 310.6+312.9 (M+H+).
Reaction SMILES: CC(OO)=[O:3].[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][C:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=1>C(O)(=O)C.ClC(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]23[O:3][C:13]2([C:19]([O:21][CH3:22])=[O:20])[C:14]([CH3:18])([CH3:17])[CH2:15][CH2:16]3)=[CH:23][CH:24]=1
Reactant: COC(=O)C1=C(Cc2ccc(Cl)cc2)CCC1(C)C
Reactant: CC(=O)OO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C12OC1(Cc1ccc(Cl)cc1)CCC2(C)C

Procedure:
23.5 g (3 equivalents) "PROXITANE 4002" (Trade Mark: 36-40% (w/w) peracetic acid in acetic acid) were added to 9.8 g (35.1 mmols) 1-(4-chlorobenzyl)-3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene prepared as described in Example 1 (f) in 90 ml trichloromethane. The resulting mixture was refluxed for 3 hours and then extracted twice with 50 ml aliquots of trichloromethane, backwashed once with 50 ml dilute aqueous sodium bicarbonate solution and twice with 50 ml aliquots of saturated aqueous sodium metabisulphite solution, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate and flashed to give 12 g of a pale yellow oil which crystallised on cooling. Trituration in 30/40 petroleum gave 5.8 g 1-(4-chlorobenzyl)-1,2-epoxy-3,3-dimethyl-2-methoxy-carbonylcyclopentane as a white crystalline solid, m.pt. 86°-87° C. Yield 56%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: BrC1CCC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CCC2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
2.50 g (14.5 mmol) 4-bromophenol, 2.05 mL (21.7 mmol) cyclobutylbromide and 7.99 g (57.8 mmol) K2CO3 are dissolved in 25 mL DMF and stirred at 120° C. for 12 h. Afterwards the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried over MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: OC([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(C)C(=O)C.[CH3:13][C:14](=[O:18])[C:15](=[O:17])[CH3:16].C1([Mg]Br)C=CC=CC=1>>[CH3:16][CH:15]([C:14](=[O:18])[CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:17]
Reactant: CC(=O)C(C)=O
Reactant: CC(=O)C(C)(O)c1ccccc1
Agent: Br[Mg]c1ccccc1
Product: CC(O)C(=O)Cc1ccccc1
Yield: 30 %

Procedure:
The preparation of 3-hydroxy-3-phenylbutan-2-one by reaction of 2,3-butanedione with an appropriate Grignard reagent is described in an article by Lapkin and Golovkova in Zuhr. Obshchei Khim (J. Gen. Chem.) 19, 701-6 (1949) and abstracted in Chemical Abstracts 44, 1057h (1950). The reaction of biacetyl with phenylmagnesium bromide (31.4 g) gave 30% methylphenylacetylcarbinol. The reaction conditions are not specifically described but earlier in the abstract the solvent used was diethyl ether and the reactants were heated for 10 hours. The preparation is also referred to in Beilsteins Handbook (1969) at page 458.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[CH:9]1([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=2)[CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: O=Cc1cc(Br)co1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cc(C2CC2)co1
Yield: 30.9 %

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carbaldehyde (300 mg, 1.71 mmol) and cyclopropylboronic acid (171 mg, 1.99 mmol), using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in toluene (7.5 mL) and water (0.5 mL), and triphenylphosphine was replaced with tricyclohexylphosphine (48 mg, 0.17 mmol). Purification by flash chromatography (0-60% EtOAc in heptane) provided 4-cyclopropylfuran-2-carbaldehyde as an orange oil 72 mg (31%). 1H NMR (400 MHz, CDCl3) δ ppm 0.55-0.61 (m, 2H), 0.90-0.97 (m, 2H), 1.69-1.77 (m, 1H), 7.00 (d, J=0.78 Hz, 1H), 7.49 (d, J=0.59 Hz, 1H), 9.58 (d, J=0.49 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[CH2:13]([N:15]1[CH2:19][CH:18]2[O:20][CH:17]2[CH2:16]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].C(O)(C)C>O>[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][CH:17]([OH:20])[CH:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][CH:17]([OH:20])[CH:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CCN1CC2OC2C1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCN1CC(O)C(Oc2ccc(C(C)=O)cc2OC)C1

Procedure:
A mixture of 17.0 g. (0.15 mole) of acetovanillone and 1-ethyl-3,4-epoxypyrrolidine and 3 drops of water was heated on a steam bath overnight. The mixture was dissolved in 250 ml. of methylene chloride and extracted with three 150-ml. portions of 5% sodium hydroxide and one 100-ml. portion of water. The methylene chloride layer wad dried over anhydrous sodium sulfate and concentrated to give 19.0 g. crude oil. This oil was chromatographed on 400 g. of silica gel. The desired product was eluted with acetone. The fractions were concentrated to give 14.0 g. of oil which was treated with oxalic acid in isopropyl alcohol. The resulting white solid was recrystllized twice from isopropyl alcohol to yield 13.4 g. (24%) of sesquioxalate, m.p. 121°-3° C.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([N:19]=[C:20]=[S:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)([OH:4])(=[O:3])=[O:2].[Na:22].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C[N:37](C)CC=C>O>[S:1]([C:5]1[CH:6]=[C:7]([NH:19][C:20]([NH2:37])=[S:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:10][CH:9]=2)([OH:4])(=[O:3])=[O:2].[Na:22]
Reactant: O=S(=O)(O)c1ccc2c(N=C=S)cc(S(=O)(=O)O)cc2c1
Reactant: C=CCN(C)C
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Temperature: 53 °C

Procedure:
Solid sodium 3,6-Disulfonapthylisothiocyanate (200 mg; 0.51 mmol) was added to a solution of poly-L-lysine (15-30K) (50 mg) in a mixture of water (2 ml) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 2 ml). The resulting mixture was heated under nitrogen at 53° C. for 3 hours, when a ninhydrin test was negative. The cooled mixture was filtered and the filtrate concentrated to give a brownish solid residue. The solid residue was redissolved in water and passed through a column of Amberlite IR 120(Na) and then concentrated. The crude product was purified by gel filtration (Sephadex LH20; water) and freeze dried to give sodium 3,6-disulfonaphthylthiourea terminated poly-L-lysine BRI6047 as a white fluffy solid (87 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:32])[CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCNCC2=O)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1
Reaction time: 16 h

Procedure:
120 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide was dissolved in 2 mL of DMF and then treated with 53 mg of paraformaldehyde, 187 mg of sodium triacetoxyborohydride and 0.2 mL of AcOH. After stirring 16 h, the reaction mixture was evaporated and the crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methyl-2-oxopiperazin-1-yl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.C(O[C:38](=[O:40])[CH3:39])(=O)C>ClCCl.C1COCC1>[OH:40][CH2:38][CH2:39][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (30 mg, 0.07 mmol, Example 26a) was dissolved in dichloromethane (1 mL) and THF (1 mL). Acetic anhydride (6.61 μL, 0.07 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated under reduced pressure, the crude was dissolved in dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (5.9 mg, 17.91%).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1.Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:25]3[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(OCC)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)s4)c3n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.19) (313 g, 1.0 mmol) and commercially available 5-bromothiophene-2-sulfonamide (315 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (160 mg, 34%). MS (ISP) 489.2 [(M+NH4)+]; mp 214° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:38]=1>CN(C=O)C>[C:49]([O:48][C:46]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([CH2:36][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:38]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a stirring solution of 437.3 mg 2-(2,4-Dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (0.95 mmol) in 10 mL DMF at 0° C. is added 2.09 mL (1.04 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2. The reaction is allowed to warm to RT, then cooled back down to 0° C., and 325 mg (1.04 mmol, 1.1 equiv) 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole is then added in one portion. The reaction is allowed to warm to RT, and is stirred an additional 20 min. The reaction is then concentrated, diluted with H2O, and the aqueous layer is extracted with ethyl acetate (3×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography (gradient 1:1-2:1 ethyl acetate:hexanes) to afford 487 mg of the title compound as a pale yellow foam: 1H NMR (CDCl3, 400 MHz) δ8.58 (s, br, 2H), 8.01 (d, 1H, J=8.4), 7.93 (d, 1H, J=7.8), 7.47 (t, 1H, J=7.5), 7.38-7.26 (m, 4H) 7.26-7.11 (m, 4H), 6.94 (dd, 2H, J=8.7, 11.8), 4.94 (m, 1H), 4.39 (s, br, 1H), 4.32 (dd, 1H, J=4.9, 8.5), 4.16 (d, 1H, J=16.6), 3.83 (s, 3H), 3.80 (m, 1H), 3.52 (dd, 1H, J=5.1, 16.5), 1.62 (s, 9H), 1.03 (d, 6H, J=6.9); low resolution MS (FAB)m/e 689 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH2:25][CH3:26])[CH2:24][O:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[NH:41][C:40](=[O:42])[O:39][N:38]=2)=[CH:33][CH:32]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH2:25][CH3:26])[CH2:22][O:23][CH2:24]3)[C:17]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:35][CH:36]=3)=[O:19])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1
Reactant: CCC1(CC(C(=O)O)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)COC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCC1(CC(C(=O)Nc2ccc(-c3noc(=O)[nH]3)cc2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)COC1
Reaction time: 0.58 h

Procedure:
37.4 mg (89.6 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)propanoic acid (racemate), 15.9 mg (89.6 μmol) of 3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one, 12.7 mg (89.6 μmol) of Oxima and 14.0 μl (89.6 μmol) of DIC in 950 μl of dimethylformamide were reacted according to General Method 5. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 nm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)] and then using Method 10. Yield: 2 mg (4% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([NH2:22])=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N[C@H](Cc2ccccc2)C(N)=O)cc1Br
Yield: 23.3 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (255 mg, 1.27 mmol), D-phenylalanine amide (220 mg, 1.34 mmol) and DIEA (0.466 mL, 2.68 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. The mixture was then purified by HPLC to give (R)-2-(3-bromo-4-cyanophenylamino)-3-phenylpropanamide (102 mg).
Reaction SMILES: [CH3:1][S:2]([CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:1][S:2][CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12]
Reactant: CS(=O)C=C1C(C)(C)CCC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSC=C1C(C)(C)CCC1(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
20 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfoxide was dissolved in 200 ml of tetrahydrofuran, and 4.0 g of lithium aluminum hydride was added thereto in small portions. The mixture was stirred at room temperature for 10 hours, and then 100 ml of ethyl acetate was added dropwise thereto. After the mixture was subjected to filtration, the filtrate was concentrated under reduced pressure. The oily substance was subjected to silica gel column chromatography using ethyl acetaten-hexane as an eluent, whereby 13.8 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfide was obtained as an oily substance.