Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: Fc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1Cl
Yield: 68.7 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (270 mg, 69%). MS (ISP) 393.1 [(M+H)+]; mp 190° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:27])[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([C:40]#[N:41])=[CH:37]2)=[CH:32][CH:31]=1>>[C:22]([C:21]1[CH:20]=[C:19]([CH2:18][N:10]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]([CH2:29][C:30]3[CH:39]=[C:38]4[C:33]([CH:34]=[CH:35][C:36]([C:40]#[N:41])=[CH:37]4)=[CH:32][CH:31]=3)[C:9]2=[O:27])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Reactant: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1
Product: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)n(Cc3ccc4ccc(C#N)cc4c3)c2=O)c1

Procedure:
In a manner similar to Preparation 2 above, 3-[(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl]benzonitrile was reacted with 7-(bromomethyl)-naphthalene-2-carbonitrile to give 7-[[3-(3-cyanophenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl]methyl]naphthalene-2-carbonitrile; NMR (CDCl3) 8.05 (s,1), 7.9 (d,1), 7.85 (d,1), 7.55 (m,3), 7.4 (m,2), 7.2 (m,9), 7.0 (m,3), 5.1 (s,2), 4.95 (s,2) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13](=[S:15])[NH2:14])=O)=[CH:4][CH:3]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:15][C:13]([NH2:14])=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)NNC(=O)Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nnc(Cc2ccc(F)cc2)s1
Yield: 75.6 %

Procedure:
0.38 g of 2-[(4-fluorophenyl)acetyl]hydrazinecarbothioamide (1.67 mmol) is added portionwise with stirring. After stirring for 3 hours between 0 and −10° C., water is added dropwise and the mixture is then returned to basic pH with sodium hydroxide, while maintaining a temperature of between 0 and −10° C. The precipitate is filtered off, washed with water and dried. 0.264 g of 5-(4-fluorobenzyl)-1,3,4-thiadiazol-2-amine is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][C:7]=1[NH2:8].C1(N)C(F)=C(F)C(F)=C([NH2:22])C=1F.[ClH:25].Cl.Cl>C(O)C>[ClH:25].[ClH:25].[NH2:22][C:2]1[CH:3]=[N:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][C:7]=1[NH2:8]
Reactant: CC(C)(C)c1cc(N)c(Br)cn1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)c(N)cn1

Procedure:
Procedure analogous to 4) S18 using 22.9 g (100 mmol) of 3-bromo-4-amino-6-tert-butylpyridine (S40) instead of 29.5 g (100 mmol) of 2-(2-bromo-4-fluorophenyl)-D4-benzimidazole (S9). The crude product is converted into the dihydrochloride by dissolution in 100 ml of ethanol and introduction of gaseous hydrochloric acid. The crystals obtained in this way are filtered off with suction and dried in vacuo. Yield: 13.3 g (56 mmol), 56%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:10]Br.O>CCOCC.C1(SC2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[C:7]=1[Br:10]
Reactant: BrBr
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: Oc1cc(Cl)c(Br)c(Cl)c1
Reaction time: 15 h
Yield: 60 %

Procedure:
81.5 g of 3,5-dichlorophenol and 2.5 g of diphenyl sulfide are dissolved in 1 liter of anhydrous ether. Then 2.5 g of anhydrous aluminium chloride are added and 80 g of bromine are added dropwise at room temperature in the course of 10 minutes. The reaction mixture is then stirred for 15 hours at reflux temperature and subsequently poured into water. The organic phase is separated, washed neutral with water, dried and concentrated. The solid residue is recrystallised from cyclohexane, affording 72.6 g of 3,5-dichloro-4-bromophenol in the form of colourless crystals with a melting point of 118°-120° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:54]([O:63][CH3:64])(=[O:62])[C:55]1[C:56](=[CH:58][CH:59]=[CH:60][CH:61]=1)[NH2:57]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:64][O:63][C:54](=[O:62])[C:55]1[CH:61]=[CH:60][CH:59]=[CH:58][C:56]=1[NH:57][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1N
Reactant: CCc1ccc(C=Cc2n[nH]c3cc(Cl)ccc23)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CCc1ccc(C=Cc2n[nH]c3cc(Nc4ccccc4C(=O)OC)ccc23)nc1
Yield: 38.3 %

Procedure:
1,2-Dimethoxymethane (2 mL) was added to 6-Chloro-3-[2-(5-ethyl-pyridin-2-yl)-vinyl]-1H-indazole (130 mg, 0.354 mmol), tris(dibenzylideneacetone)dipalladium (16 mg, 0.018 mmol), -(dicyclohexylphosphino)biphenyl (25 mg, 0.071 mmol), K3PO4 (0.188 g, 0.885 mmol), and methyl anthranilate (0.092 mL, 0.71 mmol). The reaction was vacuum flushed with argon (4×) and then heated to 80 degrees Celsius for 19 hours. The reaction was diluted with EtOAc (20 mL) and filtered through a silica gel plug. After washing with EtOAc (50 mL), the solvent was removed by rotary evaporation. The crude oil was purified by chromatography (40 g silica gel, 30–40% EtOAc/hexanes) to yield the desired product (54 mg, 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][NH:26]C(=O)OCC5C=CC=CC=5)[CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.[H][H]>O1CCCC1.CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCCNC(=O)OCc4ccccc4)C3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCCN)C3)cc12

Procedure:
To a solution of Example 127 (100 mg, 0.194 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL) was added 20% palladium hydroxide on carbon (wet, 20 mg, 0.015 mmol). The mixture was heated under 50 psi hydrogen at 45° C. for 3 hours and cooled. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by reverse phase HPLC, and was eluted with 10-70% acetonitrile in 0.1% trifluoroacetic acid/water to afford the title compound. LCMS: 383.23 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.74 (m, 3H) 1.82-1.93 (m, 1H) 1.95-2.07 (m, 2H) 2.18 (d, 1H) 2.81-2.97 (m, 4H) 3.14-3.23 (m, 2H) 3.48 (t, 2H) 3.74 (s, 3H) 6.10 (s, 1H) 7.08 (d, 1H) 7.17-7.23 (m, 2H) 7.25-7.34 (m, 1H) 8.22 (d, 1H) 10.17 (s, 1H) 11.88 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:18][CH:17]([CH2:25][C:26]([OH:28])=[O:27])[C:16]1=[O:29])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)([CH3:32])[CH3:31].Cl>C(Cl)Cl.C(N(CC)CC)C>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][N:22]([C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([CH:30]([CH3:31])[CH3:32])=[CH:34][CH:35]=3)[CH2:23][CH2:24]2)[S:18][CH:17]([CH2:25][C:26]([OH:28])=[O:27])[C:16]1=[O:29])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: O=C(O)CC1SC2(CCNCC2)N(Cc2ccccc2)C1=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C(=O)N2CCC3(CC2)SC(CC(=O)O)C(=O)N3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 5 ml of methylene chloride was suspended 0.25 g of 4-isopropylbenzoic acid. Then, at ambient temperature, 0.12 ml of thionyl chloride and 0.03 ml of N,N-dimethylformamide were added. After stirring the mixture at the same temperature as above for one hour, the solvent was distilled off under reduced pressure, and an azeotropic distillation treatment using toluene was carried out to obtain 0.25 g of 4-isopropylbenzoic acid chloride. To a suspension of 0.50 g of trifluoroacetic acid salt of 2-(4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid in 5 ml methylene chloride were successively added dropwise at 0-5° C. 0.64 ml of triethylamine and a solution of 0.25 g of 4-isopropylbenzoic acid chloride in 5 ml methylene chloride. The resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=1:1, followed by chloroform] gave 0.30 g of 2-[4-benzyl-8-(4-isopropylbenzoyl)-3-oxo-1-thia-4,8-diazaspiro[4.5]-decan-2-yl]-acetic acid as a light yellow solid product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[N:34]1([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl>CCO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]4[CH:42]=[CH:41][C:40]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:46][CH:45]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1)c1c(F)cccc1F
Temperature: 80 °C
Yield: 43 %

Procedure:
To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (100 mg, 0.216 mmol.) in 1 mL of EtOH, added 4-(4-morpholinyl)aniline (38 mg, 0.216 mmol.) and 5 μL of conc. HCl. The reaction contents were heated to 80° C. After heating for 18 h, the reaction was cooled to rt and partitioned between EtOAc and sat. aq. NaHCO3. The layers were separated, extracted the aqueous layer with EtOAc (2×10 mL), the organic layers were pooled, dried over MgSO4, filtered, reduced in vacuo onto silica. Purified via ISCO chromatography (hexanes:EtOAc) to afford the desired compound as a yellow solid, 56 mg, 43% yield. 1H NMR (400 MHz, CD3OD): δ 8.61 (d, J=7 Hz, 1H); 8.40 (d, J=9 Hz, 1H); 8.14 (d, J=5 Hz, 1H); 7.98 (bs, 1H); 7.86 (d, J=7H, 1H); 7.56-7.48 (m, 3H); 7.48-7.37 (m, 3H); 7.12-7.05 (m, 3H); 6.92 (d, J=9 Hz, 2H) 6.58 (d, J=5 Hz, 1H); 3.85-3.83 (m, 4H); 3.11-3.09 (m 4H). HRMS calculated C34H28F2N7O2 [M+H]+ 604.2273, found 604.2271.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[C@@H:17]([NH:18]C(=O)OCC2C=CC=CC=2)[CH2:16][C@H:15]2[C@@H:13]1[CH2:14]2.C[Si](I)(C)C>C(Cl)(Cl)Cl>[NH2:18][C@H:17]1[CH2:16][C@H:15]2[C@H:13]([CH2:14]2)[C@H:12]1[N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl (1S,2R,3S,5S)-2-(1,3-dioxoisoindolin-2-yl)bicyclo[3.1.0]hexan-3-ylcarbamate (4.0 g, 10.638 mmol) in chloroform (30 mL) at room temperature was added trimethylsilyl iodide (14.6 mL, 106.380 mmol) dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with methanol (5 mL), diluted with ethyl acetate (150 mL), and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford a crude compound, which was directly used in the next reaction without further purification. MS (ES+) C14H14N2O2 requires: 242, found: 243 [M+H]+.
Reaction SMILES: C([O:9][CH2:10][C:11]([CH3:33])([CH3:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[CH:22]=[N:21]2)=[CH:16][C:15]=1[C:30]#[N:31])(=O)C1C=CC=CC=1.[OH-].[Na+].O.Cl>C(O)C>[C:30]([C:15]1[CH:16]=[C:17]([N:20]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[N:21]2)[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:11]([CH3:33])([CH3:32])[CH2:10][OH:9])#[N:31]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)COC(=O)c3ccccc3)c(C#N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CO)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 50 °C
Yield: 14.7 %

Procedure:
To a solution (20 ml) of ethyl 1-(4-(3-benzoyloxy-2,2-di methylpropoxy)-3-cyanophenyl) pyrazole-4-carboxylate (2.89 g) obtained in Example 37 in ethanol was added 1 N aqueous sodium hydroxide solution (14.2 ml) with stirring, and the mixture was heated at 50° C. for 3 hours. After the completion of the reaction, the reaction mixture was poured into water and neutralized with 1 N hydrochloric acid (15 ml). The precipitated crystals were recrystallized from ethyl acetate to give 0.3 g of 1-(3-cyano-4-(2,2-dimethyl 3-hydroxypropoxy)phenyl)pyrazole-4-carboxylic acid, melting point 188-190° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][Mg]Br.C(OCC)C>O1CCCC1>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:12])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: C[Mg]Br
Reactant: CSc1ncc(C=O)c(N)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ncc(C(C)O)c(N)n1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a suspension of 5.0 g (29 mmol) 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3) in 150 mL of tetrahydrofuran, cooled by an ice bath, is added during 20 minutes. 23.2 mL of a 3.0 M methylmagnesium bromide solution in diethyl ether (69.4 mmol). After 1 hour at 0° C. another 23.2 mL of the 3.0 M methylmagnesium bromide solution is added, and the suspension is allowed to come to room temperature and stirred overnight. The reaction is quenched with 100 mL of saturated aqueous ammonium chloride, and partitioned between water and ethyl acetate. The organic layer is dried (magnesium sulfate) and concentrated to give 5.24 g (96%) of the product, mp 140-142° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[O:26][C:25](=[O:27])[C:24]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[N:23]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([NH:23][C:24]1([C:25]([NH:10][C@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13])=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)c2ccco2)CCCCC1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A solution of 8.81 ml (50.6 mmol) of N,N-diisopropylethylamine, and 2.09 g (20.2 mmol) of L-valinol in 10 mL of methylene chloride was added to a solution of 3.71 g (16.9 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 100 ml of toluene, and the mixture was heated under reflux for 14 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was stirred overnight. The obtained crystal was collected by filtration to obtain 4.06 g (74.7%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Br)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[C:24]([Si:28]([O:31][C:32]([CH3:36])([CH3:35])[C:33]#[CH:34])([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>C(NC(C)C)(C)C.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.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([C:34]#[C:33][C:32]([O:31][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])([CH3:36])[CH3:35])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)c1c(Br)cc(-c2c(CC)cccc2CC)nc1C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C#CC(C)(C)O[Si](C)(C)C(C)(C)C)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 105 °C

Procedure:
A mixture of 4-bromo-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic ethyl ester (274 mg, 0.73 mmol), tert-butyl-(1,1-dimethyl-prop-2-ynyloxy)-dimethyl-silane (724 mg, 0.37 mmol), Pd(PPh3)4 (84 mg, 0.082 mmol), and copper iodide (7 mg, 0.037 mmol) in diisopropylamine (8 mL) is heated at 105° C. in a sealed tube. The filtrate is concentrated in vacuo. The residue is purified by flash chromatography to give 4-[3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-but-1-ynyl]-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester as a pale yellow oil. 1H NMR (CDCl3) 7.38-7.31 (m, 2H), 7.17-7.12 (m, 2H), 4.43 (q, 2H), 2.62 (s, 3H), 2.38-2.25 (m, 4H), 1.56 (s, 6H), 1.44 (t, 3H), 1.06 (t, 6H), 0.83 (s, 9H), 0.15 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34].O>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Yield: 64.5 %

Procedure:
Raltegravir (10 gm) was dissolved in dimethylformamide (100 ml) at room temperature and cooled to 10 to 15 deg C. To the reaction mass was added slowly a mixture of potassium hydroxide (1.5 gm) and water (2 ml) at 10 to 15 deg C. and the temperature was raised to 25 to 30 deg C., filtered. The solid obtained was washed with dimethylformamide and dried at 110 to 120 deg C. for 48 hours to obtain 7 gm of raltegravir potassium crystalline form H1.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[N:11][N:10]2[C:18]=1[S:19]([NH2:22])(=[O:21])=[O:20].Cl>CN(C=O)C.O>[CH2:3]([S:5][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[N:11][N:10]2[C:18]=1[S:19]([NH2:22])(=[O:21])=[O:20])[CH3:4]
Reactant: CCCc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1
Reactant: CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc2nc(SCC)c(S(N)(=O)=O)n2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, 0.73 g, 18.2 mmol) was suspended in DMF (10.0 ml) under ice-cooling, and ethanethiol (1.35 ml, 18.2 mmol) was added dropwise thereto, and the mixture was stirred at 0° C. for 2 hours. 2-Chloro-6-propylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.00 g, 3.64 mmol) was added thereto and heated at 110° C. for 2.5 hours under stirring. The reaction mixture was left, cooled, diluted with water and acidified by dropwise addition of conc. hydrochloric acid. The precipitated solids were collected by filtration and washed with water, and the solids were suspended in a mixed solvent of chloroform and ethyl acetate, and the insoluble solids were collected by filtration, and the solids were washed with chloroform to give the title compound as gray crystals. The yield was 0.45 g (41.2%).
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([N:38]([CH2:51][CH2:52][CH2:53][CH3:54])[C:39]1[CH:46]=[C:45]([O:47][CH3:48])[C:42]([CH:43]=O)=[C:41]([O:49][CH3:50])[CH:40]=1)[CH2:35][CH2:36][CH3:37].C(Cl)(Cl)Cl>O1CCCC1>[CH2:34]([N:38]([CH2:51][CH2:52][CH2:53][CH3:54])[C:39]1[CH:46]=[C:45]([O:47][CH3:48])[C:42]([CH:43]=[CH:14][C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)=[C:41]([O:49][CH3:50])[CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCN(CCCC)c1cc(OC)c(C=O)c(OC)c1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)c1cc(OC)c(C=Cc2cccs2)c(OC)c1
Temperature: 0 °C
Yield: 62.6 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 3.76 g of a 19% phenyllithium solution (8.5 mmol), and 0.78 g (1.98 mmol) of thiophene-2-ylmethyltriphenylphosphonium bromide was added thereto under cooling. After the mixture was well-stirred, 0.58 g (1.98 mmol) of 4-dibutylamino-2,6-dimethoxybenzaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 1.5 hours. After the mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 463 mg (yield: 62%) of 2-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene as a dark purple crystal (mp: 90° C.)