Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=1)=[O:5])[CH3:2].N([O-])=[O:21].[Na+].OS(O)(=O)=O>[H+].[B-](F)(F)(F)F.O>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccc(N)cc2)CC(=O)N1C
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [H+]
Solvent: O
Product: CCOC(=O)[C@H]1[C@@H](c2ccc(O)cc2)CC(=O)N1C
Temperature: 90 °C
Reaction time: 0.58 h
Yield: 89 %

Procedure:
A 2° C. solution of (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-aminophenyl)pyrrolidin-2-one (prepared according to the procedure for Intermediate U, 3.25 g, 12.4 mmol) in 42% aqueous HBF4 (6 mL) and water (6 mL) was treated dropwise with a solution of NaNO2 (856 mg, 12.4 mmol) in water (6 mL), keeping the reaction temperature below 10° C. The reaction mixture was stirred for 35 min, then poured in one portion into a 90° C. solution of H2SO4 (24 mL) in water (360 mL). The resulting solution was heated at 90° C. for 45 min, cooled to room temperature, diluted with ice (200 g) and extracted with CH2Cl2. The organic layer was dried (MgSo4) and concentrated under reduced pressure to yield (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-hydroxyphenyl)-pyrrolidin-2-one (2.90 g, 89%) as an orange oil: 1H NMR (DMSO-d6) δ 0.76 (t, J=6.4 Hz, 3H), 2.41-2.67 (m, 5H), 3.59-3.87 (m, 3H), 4.38 (d, J=8.5 Hz, 1H), 6.63-6.68 (m, 2H), 6.97-7.02 (m, 2H), 9.30 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH3:13])[CH2:8]2)=[N:5][N:6]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[CH3:13][CH:9]1[CH2:8][N:7]([C:4]2[S:3][C:2]([NH:1][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:6][N:5]=2)[CH2:12][CH2:11][O:10]1
Reactant: CC1CN(c2nnc(N)s2)CCO1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1nnc(N2CCOC(C)C2)s1)C(=O)OCC

Procedure:
2-amino-5-(2-methyl-morpholino)-1,3,4-thiadiazole (10 g) was reacted with diethyl ethoxymethylene-malonate (11.3 g) at 120° C. for 30 minutes: after cooling the reaction mixture was crystallized from isopropyl ether to give diethyl N-[5-(2-methyl-morpholino)-1,3,4-thiadiazol-2-yl]-aminomethylene-malonate, m.p. 89°-91° C. (16.4 g), which was treated with polyphosphoric acid (6.9 g) and POCl3 (27.15 g) under stirring at 120° C. for 30 minutes.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])[C:15]([N:16]([CH3:17])[CH3:18])=[O:19]
Reactant: CN(C)C(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Cl)c(F)c(CN)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (3-chloro-5-dimethylcarbamoyl-2-fluoro-benzyl)-carbamic acid tert-butyl ester (115 mg, 0.33 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL). The reaction mixture was stirred for 1 h at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC/MS): 231.0 [M]+. tR (HPLC conditions c): 2.59 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCO)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCO)cc1
Yield: 80 %

Procedure:
To a solution of (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid (1.0 g, 3.21 mmol) in methanol (10 mL) was added a catalytic amount of concentrated sulfuric acid. The reaction mixture was stirred at reflux for 3 hours. The solvent was evaporated and the crude (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid methyl ester (0.836 g, 80% yield) was carried on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[C:6]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[F:28])[CH:5]=[CH:4][N:3]=1.C1C[N:32]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH2:32])=[O:17])=[CH:12][CH:13]=2)=[C:6]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[F:28])[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1-c1ccc(CC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(-c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2N)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.5 %

Procedure:
A solution of 2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid (65 mg, 0.17 mmol) in anhydrous DMF (1.2 mL) was treated with PyBOP (125 mg, 0.24 mmol) and HOBt (32 mg, 0.24 mmol) followed by DIPEA (60 μL, 0.35 mmol) and NH4Cl (19 mg, 0.35 mmol). After stirring at room temperature for 20 min, the mixture was concentrated under vacuum and the residue partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The product was purified by flash column chromatography on SiO2 eluting with 0-8% MeOH/CH2Cl2 to give the title compound (40 mg, 62%) as an amber colored oil. 1H NMR (DMSO-d6) δ 8.23 (dd, 1H, J=10.7, 2.5 Hz), 8.05 (d, 1H, J=9.2 Hz), 7.93 (d, 1H, J=6.1 Hz), 7.42-7.32 (m, 2H), 7.33-7.25 (m, 4H), 6.92 (s, 1H), 6.25 (d, 1H, J=5.6 Hz), 5.64 (s, 2H), 3.36 (s, 2H); MS(ESI+): m/z 383.17 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(C(N[C@H](C)c2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(N[C@H](C)c2ccc(F)c(F)c2)c2cccc(N)c2)cc1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 5.88 g of N-[(R)-1-(3 4-difluorophenyl)ethyl]-N-[(3-nitrophenyl)-(p-tolyl)methyl]amine [prepared as described in step (a) above], 7.31 g of nickel chloride hexahydrate and 2.33 g of sodium borohydride were reacted, to obtain 0.91 g of isomer A and 335 mg of isomer B of the title compound, each as a colorless oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[O:64])[C:27]([NH:29][CH:30]2[C:62](=[O:63])[N:32]3[C:33]([C:46]([O:48][CH:49]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[O:47])=[C:34]([CH:37]=[CH:38][S:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]([OH:64])[C:27]([NH:29][CH:30]2[C:62](=[O:63])[N:32]3[C:33]([C:46]([O:48][CH:49]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[O:47])=[C:34]([CH:37]=[CH:38][S:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS[C@H]12)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=CSc2cccnc2)CS[C@@H]2C(NC(=O)C(O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a solution of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)glyoxylamido]-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (3.1 g) in a mixture of methanol (16 ml) and tetrahydrofuran (16 ml) was added sodium borohydride (0.033 g) under ice-cooling and the mixture was stirred for 10 minutes. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-hydroxyacetamido]-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (trans isomer) (2.84 g).
Reaction SMILES: Cl[O-].[Na+].[CH3:4][C:5]1[CH:10](/[CH:11]=[CH:12]/[C:13]([CH3:15])=[O:14])[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7][CH:6]=1.C(Cl)[Cl:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:19][CH:6]1[C:5](=[CH2:4])[CH:10]([CH:11]=[CH:12][C:13](=[O:14])[CH3:15])[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1
Reactant: ClCCl
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: C=C1C(Cl)CCC(C)(C)C1C=CC(C)=O
Reaction time: 0.5 h

Procedure:
To a mixture of commercial bleach (28.5 ml of a 5.25% solution of sodium hypochlorite), α-ionone (3.84 g), and methylene chloride (330 ml) was added a solution of potassium phosphate (monobasic) (5.44 g) in water (40 ml) during a 30 minute period. The mixture was stirred for 30 minutes at 25°, the methylene chloride solution washed with sodium bicarbonate solution and evaporated to give 4.1 g of crude product. Purification by column chromatography gave 2.35 g of 4-(5-chloro-6-methylene-2,2-dimethylcyclohexyl)-3-buten-2-one. NMR (CDCl3) δ0.90 and 0.93 (6H, 2s, >C(CH3)2), 0.9-2.1 (4H, m), 2.27 (3H, s, --COCH3), 2.53 and 2.71 (1H, 2s, >CH--CH=CH--), 4.35-4.68 (1H, m, >CHCl), 4.70, 4.83, 5.15 and 5.33 (2H, 4s, >C=CH2), 5.9-6.4 (1H, m, --CH=CH--CO--), 6.7-7.3 (1H, --CH=CH--COCH3). IR (film) νmax 2960, 1695, 1675, 1630, 1450, 1430 cm -1. MS m/e 191, 149.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 1.00 g (3.25 mmol) of 5-(Benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 630 μL (2.16 mmol) of 1-bromopentadecane in 20 mL of anhydrous THF were added 2.70 mL (4.32 mmol) of a 1.60 M solution of n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 70 mL of water. The mixture was then extracted with two 70-mL portions of diethyl ether. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-diethyl ether afforded the expected product as a colorless oil: yield 269 mg (24%); silica gel TLC Rf 0.5 (4:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ0.89 (t, 3H, J=7.2 Hz), 1.20-1.30 (m, 26H), 1.75 (quint, 2H, J=7.2 Hz), 2.29 (s, 6H), 2.47 (s, 3H), 2.76 (dd, 2H, J=8.0, 8.0 Hz), 4.89 (s, 2H), 5.85 (s, 2H) and 7.30-7.42 (m, 5H); 13C NMR (CDCl3) δ 14.08, 14.30, 14.30, 19.27, 22.66 27.72, 29.33, 29.40, 29.50, 29.55, 29.63, 29.63, 29.63, 29.67, 29.67, 29.67, 29.67, 31.61, 31.89, 75.72, 107.91, 128.01, 128.22, 128.72, 129.30, 129.30, 136.22, 147.35, 147.35, 152.59, 161.59 and 165.09; mass spectrum (APCI), m/z 518.4113 (M+H)+ (C34H52N3O requires 518.4110).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[S:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: O=C(Cl)c1ccsc1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccsc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.061 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([N:6]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)[C:7]2[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[OH2:23]>>[S:1]1[CH:5]=[C:4]([N:6]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)[C:7]2[CH:12]=[C:11]([OH:23])[CH:10]=[CH:9][CH:8]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: Oc1ccc(N(c2cc[nH]n2)c2csc3ccccc23)cc1
Reactant: O
Product: Oc1cccc(N(c2cc[nH]n2)c2csc3ccccc23)c1
Yield: 26 %

Procedure:
Prepared in 26% yield from (5-benzo[b]thiophen-3-yl)-1H-pyrazol-3-yl)-3-(methoxy-phenyl)-amine analogous to the procedure for 4-(benzo[b]thiophen-3-yl-1H-pyrazol-3-ylamino)-phenol [Example 2(b)]. 1H NMR (300 MHz, DMSO-d6) δ12.40 (s, 1H), 9.09 (s, 1H), 8.33 (s, 1H), 8.06 (d, 2 H, J=6.9 Hz), 7.98 (s. 1H), 7.42-7.51 (m, 2H), 6.96 (t, 1H, J=7.8 Hz), 6.92 (br s, 1H), 6.71 (br s, 1H), 6.26 (br s, 1H), 6.15 (d, 1H, J=7.5 Hz). Anal. (C17H13N3OS.0.33 H2O) C, H, N, S. Calculated C=65.17; H=4.39; N=13.41; S=10.23; found C=65.30; H=4.40; N=13.05; S=10.19.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([C:36]2[S:37][C:38]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:39][CH:40]=2)(=[O:34])=[O:35])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Nc1ccncc1)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncc1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid pyridin-4-ylamide (example B.57) (160 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (160 mg, 54%). MS (ISN) 592.1 [(M−H)−]; mp 209° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)c1
Yield: 91 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (117 mg), 120 mg 6-(3-methoxyphenyl)-2-oxindole and 3 drops piperidine in 3 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 190 mg (91%) of the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:39]2[C:34](=[C:35]([N:40]([CH3:42])[CH3:41])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[C:39]4[C:34](=[C:35]([N:40]([CH3:42])[CH3:41])[CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCN=[N+]=[N-])cccc12
Product: CN(C)c1cccc2c(S(=O)(=O)NCCn3cc(CCCCCc4cn(C(=O)OC(C)(C)C)c(N)n4)nn3)cccc12

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.112 g, 0.403 mmol) was reacted with N-(2-azidoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide (0.140 g, 0.403 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J=8.4 Hz, 1H), δ 8.24 (d, J=8.4 Hz, 1H), δ 8.17 (d, J=7.2 Hz, 1H), δ 7.44 (m, 3H), δ 7.09 (s, 1H), δ 7.07 (d, J=7.5 Hz, 1H), δ 6.44 (s, 1H), δ 6.09 (bs, 2H), δ 4.32 (s, 2H), δ 3.36 (s, 2H), δ 2.52 (s, 2H), δ 2.22 (s, 2H), δ 1.43 (m, 13H), δ 1.22 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 176.9, 152.1, 149.6, 148.0, 138.6, 135.1, 130.7, 130.1, 129.7, 129.4, 128.5, 123.3, 122.4, 119.1, 115.5, 84.9, 67.5, 50.3, 50.2, 45.6, 42.9, 37.9, 29.1, 28.9, 28.2, 28.0, 25.5 ppm; HRMS (ESI) calcd for C29H40N8O4S (M+) 596.2893. found 596.2881, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-5-(dimethylamino)naphthalene-1-sulfonamide hydrochloride (0.139 g, 65% yield). 1H NMR (400 MHz, CD3OD) δ 8.70 (t, J=4.8 Hz, 2H), δ 8.31 (s, 1H), δ 8.08 (s, 2H), δ 7.82 (s, 2H), δ 6.43 (s, 1H), δ 4.55 (s, 2H), δ 3.32 (s, 8H), 2.63 (s, 2H), δ 2.48 (s, 2H), δ 1.66 (s, 4H), δ 1.40 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 159.9, 147.3, 140.7, 136.8, 129.9, 129.3, 127.8, 127.7, 126.5, 119.3, 108.6, 108.4, 76.7, 67.3, 51.5, 42.3, 37.4, 36.5, 28.3, 27.9, 27.6, 24.1, 24.0, 23.7 ppm; HRMS (ESI) calcd for C24H32N8O2S (M+) 496.2369. found 496.2359.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:31][CH:30]=1
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc(CC)n(-c2ccc(Br)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 55.8 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2 g), 4-bromophenylboronic acid (2.3 g), triethylamine (3.9 mL), pyridine (2.3 mL) and molecular sieves 4 A (4 g) in dichloromethane (20 mL) was added copper(II) acetate (2.0 g) and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.6 g, 56%).
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[C:7]([F:18])[C:6]=2[O:19][CH2:20][CH:21]2[CH2:23][O:22]2)[CH2:4][CH2:3][CH2:2]1.[NH3:24]>CO>[NH2:24][CH2:23][CH:21]([OH:22])[CH2:20][O:19][C:6]1[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:10][CH:9]=[C:8]([C:11]2[CH:16]=[N:15][C:14]([NH2:17])=[CH:13][N:12]=2)[C:7]=1[F:18]
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(OCC3CO3)c2F)cn1
Reactant: N
Solvent: CO
Product: NCC(O)COc1c(C2CCC2)ccc(-c2cnc(N)cn2)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (500 mg, 1.59 mmol) and 6 N NH3 in MeOH (5 mL) was stirred in a sealed tube at 60° Celsius for approximately 8 hours before cooling to rt and concentrating to dryness to give 1-amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol (510 mg, 96%).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][CH2:15][CH2:16][OH:17]>CN(C)C=O>[Si:6]([O:17][CH2:16][CH2:15][Br:14])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Combine imidazole (59.9 g, 880 mmol), t-butyldimethylsilyl chloride (60.3 g, 400 mmol), and dimethylformamide (300 mL). Cool to 0° C. in a salt-ice bath. Add dropwise 2-bromoethanol (50.0 g, 400 mmol) at such a rate that the temperature of the reaction mixture does not rise above 0° C. After 2 hours, warm to ambient temperature. After 18 hours, extract the reaction mixture three times with hexane. Combine the hexane layers and extract three times with a saturated aqueous solution of ammonium chloride, three times with a saturated aqueous solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N-:8]=[N+:9]=[N-:10].[Na+]>[OH-].[Na+].C(O)C.C(Cl)(Cl)Cl>[N:8]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[N+:9]=[N-:10]
Reactant: Clc1ccncc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=Nc1ccncc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
4-Chloropyridine (400 mg) was dissolved in 2.6 ml of a 1M aqueous solution of sodium hydroxide and 1.5 ml of ethanol, 340 mg of sodium azide was added to the solution at room temperature and the mixture was stirred at 110° C. for 4 hours. The reaction solution was returned to room temperature, diluted with chloroform and washed with water and then a saturated saline solution. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo to give 140 mg of the crude product of the title compound.