Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: C1COCCN1
Solvent: CCO
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCOCC1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and morpholine in ethanol. EI-MS m/e (%): 271 (M+, 50), 270 ([M—H]+, 100), 240 (28), 214 (48), 213 (35), 186 (40).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:12][C:5]2[S:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[C:3]1=[O:13].[F:15][C:16]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:28])([CH3:29])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][C:17]=1[NH:18][C:9]([C:7]1[S:6][C:5]2[CH2:12][C:2]([CH3:1])([CH3:14])[C:3](=[O:13])[C:4]=2[CH:8]=1)=[O:11]
Reactant: CC1(C)Cc2sc(C(=O)O)cc2C1=O
Reactant: CC1(C)OB(c2ccc(F)c(N)c2)OC1(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2sc(C(=O)Nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)cc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 9 (270 mg, 1.29 mmol) and methylene chloride (3 mL). The solution Was cooled to 0° C., and 15 (172 mg, 1.29 mmol) was added dropwise. After this addition was complete, the reaction was warmed to room temperature and stirred for 2 h. 14 (305 mg, 1.29 mmol) was then added. After this addition, the reaction was cooled to 0° C., and anhydrous pyridine (306 mg, 3.87 mmol) was added. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 16 h. After this time, the solvents were removed under reduced pressure, and the resulting residue was partitioned between water (10 mL) and methylene chloride (20 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×10 mL). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 27 in 45% yield (235 mg) as a white solid: mp 88-89° C.; 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J=8.5 Hz), 7.87 (s, 1H), 7.62 (s, 1H), 7.56 (t, 1H, J=6.5 Hz), 7.14 (dd, 1H, J=11.0, 8.5 Hz), 3.11 (s, 2H) 1.38 (s, 12H), 1.33 (s, 6H); MS (APCI+) m/z 430.3 (M+H).
Reaction SMILES: [CH:1](B1OC(C)(C)C(C)(C)O1)=[CH2:2].C([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=2)[C:21]=1[CH3:22])=[O:16])C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.O1CCCC1>[CH2:1]([C:26]1[CH:27]=[CH:28][C:23]([N:20]2[C:21]([CH3:22])=[C:17]([C:15]([OH:14])=[O:16])[CH:18]=[N:19]2)=[N:24][CH:25]=1)[CH3:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(-n2ncc(C(=O)O)c2C)nc1
Temperature: 100 °C
Reaction time: 6.5 h

Procedure:
Vinylboronic acid pinacol ester (2.4 ml) was added to 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.1 g) described in Reference Example 24(2), palladium (II) acetate (224 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (410 mg), tripotassium phosphate (5.3 g) and tetrahydrofuran (20 ml), and stirred at 100° C. for 6.5 hours. Then palladium (II) acetate (22.4 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (41 mg), vinylboronic acid pinacol ester (240 μl) and tripotassium phosphate (530 mg) were added therein, and stirred at 100° C. for 8.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate). 1,4-Dioxane (28 ml) and 10% palladium-carbon (containing ca. 50% of water; 700 mg) were added to the purified yellow oily product and the mixture was stirred under hydrogen atmosphere at room temperature for 6 hours. The reaction solution was filtered through Celite, concentrated in vacuo and the residue was purified with silica gel column chromatography (n-hexane/ethyl acetate). 4N Aqueous solution of sodium hydroxide (5 ml), water (5 ml) and ethanol (10 ml) were added to the purified oily product and the mixture was stirred at 80° C. for 4.5 hours. The reaction solution was concentrated in vacuo and 1N hydrochloric acid aqueous solution was added to the residue at 0° C. and then the precipitated solid was washed with water to give the titled compound (1.16 g) as a gray solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21]>O1CCCC1>[OH:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20](=[O:22])(=[O:21])[NH:19][C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH:24]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.2 g, 2.85 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCO3 solution (2.3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acryloyl chloride (16e) (0.21 g) in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was washed with diethyl ether and petroleum ether-ethyl acetate (3:1) affording the title compound (0.14 g, 68%). M.p. 164° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.49 (1H, d, J=16.0 Hz); 7.16-7.89 (12H, m); 7.98 (1H, br s); 10.52 (1H, s); 10.76 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 50:50; sample concentration 0.5 mg/ml; flow rate 0.8 ml/min; detector UV 220 nm). Anal. Caled for C19H16N2O4S, %: C, 61.94; H, 4.38; N, 7.60. Found, %: C, 61.44; H, 4.39; N, 7.48.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>O>[Br:13][CH2:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([CH3:12])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cc(CBr)c1Cl
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of 129 g of 2-chloro-1,3-dimethyl-5-nitrobenzene, 125 g of 1-bromo-2,5-pyrrolidinedione, 12 g of dibenzoyl peroxide and 1200 ml of tetrachloromethane was stirred for 2 hours at reflux temperature using a water separator. Twice there was added an extra portion of 20 g of dibenzoyl peroxide during a refiuxing period of 29 hours. After cooling, the reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /hexane 50:50). The eluent of the desired fraction was evaporated, yielding 130 g (70.2%) of 1-(bromomethyl)-2-chloro-3-methyl-5-nitrobenzene (interre. 5).
Reaction SMILES: C1(PC2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.CCCCCC.[ClH:25].Cl.[CH:27]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:49]=[CH:48][C:47]([O:50]C)=[CH:46][CH:45]=3)[CH2:40][CH2:39]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>C1COCC1>[ClH:25].[ClH:25].[CH:27]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=3)[CH2:40][CH2:39]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: COc1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(Pc2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Reaction time: 0.17 h

Procedure:
A solution of diphenylphosphine (8.7 ml, 50 mmol) in THF (60 ml) is cooled to 0° under a nitrogen atmosphere and treated with n-butyllithium in hexane (1.6 M, 31.3 ml, 50 mmol). After stirring for 10 min, a solution of 4-[2-(indan-1-yl)ethyl]-1-(4-methoxyphenyl)piperazine (CXII, EXAMPLE 70, 6.73 g, 20 mmol) in THF (20 ml) is added. The mixture is refluxed for 24 hr, quenched with water and extracted with ethyl acetate (2×800 ml). The organic phase is washed with water, saline, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The concentrate is purified by liquid chromatography on silica gel 60 (230-400 mesh, 400 g), eluting with hexane/acetone (2/1). The appropriate fractions homogeneous by TLC are combined and concentrated to give the free base of the title compound. This free base is converted into the hydrochloric acid salt and recrystallized from ethyl acetate/methanol to give the title compound, mp 215-216°, NMR (DMSO-d6, TMS) 7.30-6.68 and 3.68-1.60 δ.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:26])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CN1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.Cl.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:26])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CC(=O)Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To an ice cold solution of 1.5 g (0.0043 mol) of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine in 40 mL of N-methylpyrrolidone containing 1.4 mL of N-methylmorpholine was added 1.72 g (0.0064 mol) of phenyl N-phenylphosphoramidochloridate in a single portion. The resulting mixture was stirred at 0° C. for 30 minutes. Diethyl L-glutamate hydrochloride (1.53 g, 0.0064 mol) was then added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residual solid triturated with 50 mL of 1N aqueous sodium carbonate. The mixture was filtered and the collected solid dissolved in 20 mL of chloroform. The chloroform solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness and chromatographed on silica gel. Elution with chloroform:methanol (95:5) gave 1.52 g (66%) of the title compound, which may be alternatively named as diethyl 2-acetyl-5,10-dideaza-9,10-didehydrofolate, mp> 250° C.; NMR (CDCl3Me2SO-d6) delta 1.15-1.45 (2t, 6H, J=6 Hz), 2.0-2.65(m, 4H), 2.3(s, 3H), 4.0-4.35(2q, 4H, J=6 Hz), 4.5-4.75(m, 1H), 6.7, 6.9(AB q, 2H, J=15 Hz), 7.33, 7.84(AB q, 4H, J=9 Hz), 8.25-8.38(m, 2H), 8.62(d, 1H, J=2 Hz), 11.5-12.5(br, 2H); IR (Nujol) 3320, 3150, 1730, 1680, 1630, 1600 cm-1.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([NH:27][C:28](=[O:30])[CH3:29])[CH:21]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9](COCC[Si](C)(C)C)[N:8]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[N:3]=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([NH:27][C:28](=[O:30])[CH3:29])[CH:21]=2)[O:5][C:6]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(=O)Nc1cc(-c2nc(I)c(-c3ncn(COCC[Si](C)(C)C)n3)o2)c(C)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(-c3nnc[nH]3)o2)c(C)cn1
Yield: 72.9 %

Procedure:
To a solution of N-{4-[4-iodo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.18 mg, 0.33 mmol) in 1,4-dioxane (3 mL) was added water (0.4 mL), (2-chlorophenyl)boronic acid (0.067 g, 0.43 mmol), tetrakis (triphenylphosphine) palladium(0) (0.038 g, 0.033 mmol) and cesium carbonate (0.32 mg, 0.99 mmol). The reaction mixture was allowed to stir and was subjected to microwave irradiation at 150° C. for 20 min. The mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM (5 mL) and to this solution was added TFA (2 mL). The reaction mixture was allowed to stir at rt overnight and was then concentrated. The residue was purified by column chromatography to give N-{4-[4-(2-chlorophenyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (Compound I-39) (0.095 g, 73%). LCMS (FA): m/z=395.6 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:12]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C=Cc1ccc(C#N)c(F)c1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(CO)cc1F

Procedure:
Into a cooled solution (−78° C.) of 2-fluoro-4-vinylbenzonitrile (1.3 g, 8.8 mmol; see step (i) above) in 40 mL of CH2Cl2 and 5 mL of methanol was bubbled ozone (50 L/h, 29 g/m3) for 30 min. Argon was subsequently bubbled through to remove excess ozone. Sodium borohydride (0.67 g, 0.018 mol) was added and the cooling bath was removed. The mixture was stirred and allowed to react for 1 h. The mixture was evaporated and 2M HCl was added. The mixture was extracted twice with diethyl ether and the combined ether fraction was dried (Na2SO4) and evaporated. The crude product crystallised. Yield: 1.1 g (81%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][N:23]=[C:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.FC(F)(F)C([O-])=O.CS(C)=O>C(O)(C)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH2:28][C:24](=[N:23][OH:22])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: ON=C1CCNC1
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CC(C)O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(=NO)C3)c(F)c(F)c2c1=O
Yield: 44.6 %

Procedure:
The reaction was conducted at room temperature for 3 hours in the same manner as in Example 3 except that 300 mg (1 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 535 mg (2.5 mmol) of 3-hydroxyiminopyrrolidine-trifluoroacetate were used as starting materials and 5 ml of dimethyl sulfoxide was used as the solvent for reaction. 7 ml of isopropanol was added to the reaction mixture, and the precipitate thereby formed was collected by filtration and recrystallized from a mixture of 6 ml of dimethyl sulfoxide and 6 ml of isopropanol to give 170 mg of the desired product as pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:21][C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:25][Si:24]([CH3:27])([CH3:26])[C:23]#[C:22][CH2:21][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[Si](C)(C)C#CCBr
Reactant: Cc1ccc2ccccc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCc1ccc2ccccc2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
2-Methyl-quinoline (0.28 mL, 2.09 mmol) was added dropwise to a solution of LDA (3.0 mL, 0.8 M in THF) in THF (3 mL) at −78° C. and the reaction mixture was stirred for 1 hour at −78° C. Then (3-bromo-prop-1-ynyl)-trimethyl-silane (0.39 mL, 2.51 mmol) was added to the reaction mixture, the solution was stirred for 18 hours at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 338 mg (1.33 mmol, 64%) of 2-(4-trimethylsilanyl-but-3-ynyl)-quinoline as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:38][N:37]([CH3:39])[S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)S(=O)(=O)c1cccc(N)c1
Product: CN(C)S(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N,N-dimethyl-benzenesulfonamide [CAS 6274-18-6; commercially available] according to general procedure II. Yellow solid. MS (ISP) 558.3 [(M+H)+]; mp 210° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[N:28]1([C:33]2[CH:40]=[CH:39][C:36]([C:37]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[N:20]=[C:21]([CH3:24])[S:22][CH:23]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(-n6cccn6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 24.9 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.050 g, 0.12 mmol), EtOH (2.3 mL) and DMF (0.2 mL), 4-(1H-pyrazol-1-yl)-benzaldehyde (0.023 g, 0.13 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 mL, 0.36 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH v/v 96:4 to give the title compound as a off-white solid (0.016 g, 25%); 1H-NMR (500 Mz, DMSO-d6): δ 2.63-2.71 (m, 7H), 3.65 (s, 2H, NCH2), 3.66-3.72 (m, 4H), 6.59-6.62 (m, 1H), 7.33 (s, 1H, thiazole 5-H), 7.81 (d, J=2.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.25 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.30 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.61 (d, J=2.5 Hz, 1H), 13.54 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.41 min—535/537 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 535.1028, calculated for C24H24BrN8S (M+H)+: 535.1039.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:9]2=3)[C:5](=O)[NH:4][C:3]1=[O:25].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>>[CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:9]2=3)[C:5](=[S:35])[NH:4][C:3]1=[O:25]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2c1cn(C)c(=O)[nH]c1=O
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of step (i) (0.2 g) and Lawesson's reagent (0.29 g) according to the method of example 2 step (ii). Purification was by chromatography eluting with 50% acetone in isohexane followed by trituration with isohexane/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].S(=O)(=O)(O)O.[BH4-].[Na+].[CH3:24][C:25]([CH3:27])=O>>[CH:25]([NH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:27])[CH3:24]
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccc(C(=O)c2ccccc2)c(NC(C)C)c1
Temperature: 20 °C
Yield: 95 %

Procedure:
To a solution of 63.3 gms. of 2-amino-4-methylbenzophenone in 722 mls. of acetone is added 87 gms. of 49% aqueous sulfuric acid. The mixture is cooled to 20° C. With stirring, and by portionwise addition, 31.2 gms. of sodium borohydride is added to the mixture over a period of 70 minutes. After the addition, the mixture is stirred for an additional 5 hours at 25° C. The suspended solids are filtered and then washed with 300 mls. of acetone. The acetone solutions are combined and concentrated. To the concentrate is added 200 mls. of heptane and 60 mls. of 4N ammonium hydroxide. The liquid layers are separated, then the heptane phase is washed with 20 mls. of water, extracted twice with 20 mls. of 2N sulfuric acid each time, and then washed to neutrality with water. The heptane phase is then dried over magnesiun sulphate, filtered, and concentrated under vacuum to a constant weight of 74.5 gms. or crude yield of 98%, which is shown by analysis to constitute an actual yield of about 95% of the desired 2-(N-isopropylamino)-4-methylbenzophenone.