Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.CCCCCC.[F:18][CH:19]([F:40])[C:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([CH:34]=[O:35])=[C:22]([C:36]([F:39])([F:38])[F:37])[N:21]=1.Cl>C1COCC1.O>[F:40][CH:19]([F:18])[C:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([CH:34]([OH:35])[C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)=[C:22]([C:36]([F:39])([F:37])[F:38])[N:21]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Reactant: Brc1ccsc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2ccsc2)c1CC(C)C
Temperature: -70 °C
Yield: 67.8 %

Procedure:
To a solution of 3-bromothiophene (4 g 24.5 mmol) in dry THF (80 mL) cooled to -70° C. was added dropwise 2.5M n-BuLi in hexane (11 mL, 27.5 mmol). The mixture was stirred for one-half h. A solution of methyl 2-(difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (6.6 g, 19.5 mmol) in anhydrous THF (20 mL) was added dropwise and stirring was continued for I h while the temperature was maintained at -70° C. The mixture was allowed to warm to RT and then poured into iced water, acidified with conc. HCl and extracted with methylene chloride. The extract was washed with water and brine, dried (MgSO4), and conc. The residue was purified by chromatography with 10% ethyl acetate/cyclohexane to yield 5.6 g of methyl 2-(difluoromethyl)-5-(hydroxy-3-thienylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate, a 68.9% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].C(C1C=CC=C(CCC)C=1[N+]1C=CN(C2C(CCC)=CC=CC=2CCC)C=1)CC.Cl.[F:53][C:54]1[CH:55]=[C:56]([CH:60]2[CH2:65][CH2:64][CH2:63][NH:62][CH2:61]2)[CH:57]=[CH:58][CH:59]=1.CC(C)([O-])C.[Na+]>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].O1CCOCC1>[F:53][C:54]1[CH:55]=[C:56]([CH:60]2[CH2:65][CH2:64][CH2:63][N:62]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]5[CH:21]=[CH:20][N:19]=[CH:18][N:17]=5)(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH2:61]2)[CH:57]=[CH:58][CH:59]=1
Reactant: Fc1cccc(C2CCCNC2)c1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cccc(CCC)c1-n1cc[n+](-c2c(CCC)cccc2CCC)c1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(N3CCCC(c4cccc(F)c4)C3)nccc2c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A vial was charged with 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate GG; 0.200 g, 0.624 mmol), Pd2(dba)3 (0.029 g, 0.031 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (0.027 g, 0.062 mmol), 3-(3-fluorophenyl)piperidine hydrochloride (0.202 g, 0.935 mmol) and sodium tert-butoxide (0.240 g, 2.494 mmol). Dioxane (6.24 ml) was added and the reaction was flushed with argon and stirred at 130° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-10% MeOH:DCM) to afford 1-(3-(3-fluorophenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.57 (s, 1H), 8.48 (s, 1H), 8.29-8.25 (m, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.19 (d, J=5.7 Hz, 1H), 7.95 (dd, J=1.8, 8.9 Hz, 1H), 7.57 (d, J=5.8 Hz, 1H), 7.35 (dt, J=6.5, 8.0 Hz, 1H), 7.25-7.16 (m, 2H), 7.08-6.97 (m, 2H), 3.79 (t, J=13.0 Hz, 2H), 3.21-3.10 (m, 1H), 3.08-2.91 (m, 2H), 2.09-1.99 (m, 1H), 1.97-1.83 (m, 2H), 1.79-1.65 (m, 1H). m/z (ESI) 464.2 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.[Mg].ClC(C)C.Cl[CH:12]([CH3:15])[CH2:13][OH:14].BrCC(Br)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([C:32]#[N:33])[CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>O1CCCC1>[NH2:33][CH:32]([C:28]1([C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=2)[CH2:29][CH2:30][CH2:31]1)[CH2:15][CH2:12][CH2:13][OH:14]
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Reactant: CC(Cl)CO
Agent: CC(Br)CBr
Agent: CC(C)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: NC(CCCO)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of isopropylmagnesium chloride [prepared by the reaction of magnesium (2.4 g) and 2-chloropropane (10 ml) in tetrahydrofuran (30 ml)] was added dropwise under argon at -20° C. to a solution of 2-chloropropan-1-ol (9.45 g) in tetrahydrofuran (100 ml). Magnesium (3.6 g) was added and the mixture was allowed to stand for twenty minutes and was then heated under relux in the presence of 1,2-dibromopropane for 40 minutes. 1-(4-Chlorophenyl)cyclobutanecarbonitrile (9 g) was added and the mixture was heated under reflux for 16 hours. The mixture was cooled and the supernatant liquid decanted from excess magnesium metal and treated with sodium borohydride (3 g) and propan-2-ol (100 ml). The mixture was heated under reflux for 5 hours. The reaction mixture was cooled, added to water and excess concentrated hydrochloric acid was added. The resulting solution was washed with toluene, basified and extracted with toluene. The extracts were dried and evaporated to give a residue which was distilled in a Buchi Kugelrohr apparatus (140°/0.4 mm) to give 4-amino-4-[1-(4-chlorophenyl)cyclobutyl]butan-1-ol.
Reaction SMILES: C(=O)([O-])[O-].[NH4+].[NH4+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH:24]=[C:23]([NH:25][C:26]3[N:31]=[C:30]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:40][C:41](O)=[O:42])[C:29]([C:44]([F:47])([F:46])[F:45])=[CH:28][N:27]=3)[CH:22]=[N:21]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C1C=CC2N(O)N=[N:54]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl>CCN(CC)CC.CN(C=O)C>[NH2:54][C:41](=[O:42])[CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][CH2:32][C:30]1[C:29]([C:44]([F:45])([F:46])[F:47])=[CH:28][N:27]=[C:26]([NH:25][C:23]2[CH:22]=[N:21][N:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:13])[CH2:15][CH2:16]3)[CH:24]=2)[N:31]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1

Procedure:
Ammonium carbonate (903 mg 9.40 mmol) was added to a suspension of 2-(2-(2-(2-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A136) (270 mg, 0.470 mmol), HOBt (317 mg, 2.35 mmol) and EDCl.HCl (450 mg, 2.35 mmol) in Et3N (1.0 mL) and DMF (25 mL) and the resulting solution was stirred at 40° C. overnight. The volatiles were removed in vacuo and the resulting residue was dissolved in EtOAc (250 mL) and washed with water (250 mL). The organics were adsorbed onto silica gel and the product was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% MeOH in EtOAc) to yield the title compound (A137) as a white solid (171 mg, 63%). LCMS-A: rt 6.481 min; m/z 574.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1>>[C:29]([C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:6][CH2:5]3)=[O:2])=[CH:26][CH:27]=1)(=[O:30])[NH2:31]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C(N)=O)cc3)(CC1)CC2
Yield: 19.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminobenzamide (46.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-carbamoylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (13.2 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([N+:14]([O-])=O)[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1.CO.O.Cl>[Fe].C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]2[C:5](=[C:6]([NH2:14])[CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1n[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Nc1cc(N)c2[nH]nc(N)c2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 19.4 %

Procedure:
A mixture consisting of 6 g of the 3-amino-5,7-dinitroindazole, 18 g of iron powder, 60 ml of methyl alcohol, 30 ml of water and 3 ml of hydrochloric acid was stirred for 1.5 hours at 70° C. After cooling the reaction mixture, the mixture was filtered. The pH of the filtrate was adjusted to 11 with a potassium carbonate solution, and the filtrate was extracted three times with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 0.85 g of 3,5,7-triaminoindazole having the following analytical values in a yield of 19%.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C@H:11]([CH2:13][CH3:14])[CH3:12])[CH:5]=1.[OH-].[Na+].Cl>CO>[C@@H:11]([NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=1)[C:3]([OH:15])=[O:2])([CH2:13][CH3:14])[CH3:12]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)ccn1

Procedure:
Treat a solution of (S)-2-sec-butylamino-isonicotinic acid methyl ester (2.69 g, 12.5 mmol) in methanol (35 mL) with 1 N NaOH (15 mL, 15 mmol) at room temperature for 5 hr. Acidify to about pH=3 with 1 N HCl. Concentrate and redissolve the residue in a 1:1 CH3CN:water solution and lyophilize to give the title compound.
Reaction SMILES: [S:1]1[C:5]([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH2:15])=[N:4][CH:3]=[N:2]1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[S:1]1[C:5]([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:15][S:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:22])=[N:4][CH:3]=[N:2]1
Reactant: Nc1cccc2cc(-c3ncns3)[nH]c12
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cc(-c3ncns3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a mixture of 2-(1,2,4-thiadiazol-5-yl)-1H-indole-7-amine (0.35 g) and pyridine (8 ml) was added thiophene-2-sulfonyl chloride (0.34 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (0.25 g, yield 43%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 232-233° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([OH:7])=[CH:5][CH3:6].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[CH2:24]([O:8][CH2:3][CH:4]([OH:7])[CH:5]=[CH2:6])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CC=C(O)CO
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(O)COCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 18.5 q of washed sodium hydride in 500 ml of dry dimethylformamide in a water bath is added dropwise, 67.4 q of 2-butene-1,2-diol. A solution of 235 g of hexadecylbromide in 100 ml of dimethylformamide is added dropwise. This mixture is stirred at room temperature for 2 days then poured into water and extracted with ether. The ether extract is separated, dried, evaporated and purified by chromatography, to give 30 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13]O)[CH2:8]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][N:40]3[C:39](=[O:41])[C:38]4=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]4[C:36]3=[O:46])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC1CCCN(Cc2ccc(Cl)cc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1CCCN(Cc2ccc(Cl)cc2)C1
Reaction time: 1.5 h
Yield: 150.1 %

Procedure:
To a solution of 1-(p-chlorobenzyl)-3-hydroxymethyl piperidine (4.0 g, 19 mmol) in THF (40 ml) were added successively triphenylphosphine (5.60 g, 21.3 mmol), phthalimide (3.14 g, 21.4 mmol) and diethyl azodicarboxylate (3.4 ml, 21 mmol) under ice-cooling and the mixture was stirred for 1.5 hours. The solvent was distilled off from the reaction mixture under reduced pressure to give 10.52 g of crude 1-(p-chlorobenzyl)-3-phthalimidomethylpiperidine. This compound was used for the subsequent reaction without purification.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC(OC)=CC=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:28]([CH2:31][CH:32]1[CH2:36][C:35]2[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:34]=2[O:33]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[CH3:42][O:41][C:39]1[CH:38]=[CH:37][C:35]2[CH2:36][CH:32]([CH2:31][NH2:28])[O:33][C:34]=2[CH:40]=1
Reactant: COc1ccc2c(c1)OC(CN=[N+]=[N-])C2
Agent: [Pd]
Agent: COc1ccc2c(c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [N-]=[N+]=[N-]
Product: COc1ccc2c(c1)OC(CN)C2
Yield: 69 %

Procedure:
Treatment of (±)-(6-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 2.99 mmol) with sodium azide (0.78 g, 11.96 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-6-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.06 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.442 g (69%) of (±)-1-(6-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp >220° C.; Anal. calcd. for C10H13NO2HCl: C, 55.69; H, 6.54; N, 6.49. Found: C, 55.29; H, 6.48; N, 6.38.
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[N:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[S:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[N:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[S:27][CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Reactant: FC(F)(F)c1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 4-(chloromethyl)-2-(trifluoromethyl)thiazole (172 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (141 mg).
Reaction SMILES: C#C.[CH2:3]([Li])[CH2:4]CC.C[O:9][C:10]1[CH2:28][CH2:27][C@H:26]2[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:25]2[CH2:24][CH2:23][C@@:20]2([CH2:21][CH3:22])[C@H:16]3[CH:17]=[CH:18][C:19]2=[O:29])[CH:11]=1.C(O)(=O)C(O)=O>O1CCCC1.O.CO>[C:3]([C@:19]1([OH:29])[CH:18]=[CH:17][C@H:16]2[C@H:15]3[C@H:25]([CH2:24][CH2:23][C@:20]12[CH2:21][CH3:22])[C@@H:26]1[C:27](=[CH:28][C:10](=[O:9])[CH2:11][CH2:12]1)[CH2:13][CH2:14]3)#[CH:4]
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1C=CC2=O
Reactant: [Li]CCCC
Agent: C#C
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
At 0° C., acetylene is introduced for 15 minutes into a solution of 40 ml of n-butyllithium (15% in hexane) in 100 ml of absolute tetrahydrofuran and then 4.0 g of 3-methoxy-18-methyl-3,5,15-estratrien-17-one in 40 ml of tetrahydrofuran is added dropwise thereto. After 15 minutes, the mixture is combined with 8 ml of water, 40 ml of methanol and 8 g of oxalic acid, stirred for one hour at 60° C., 600 ml of water is added, and the mixture is extracted with ethyl acetate. The organic phase is washed with water and dried. Recrystallization from ethyl acetate yields 2.4 g of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one. Melting point 197° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:14]([Cl:28])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:28][C:14]1[CH:13]=[N:12][C:11]2=[N:16][C:15]=1[NH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([O:27][CH2:2][CH2:3][C:4]3[CH:5]=[C:6]([NH:10]2)[CH:7]=[CH:8][CH:9]=3)[CH:24]=[CH:25][CH:26]=1
Reactant: Oc1cccc(CCCNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc2nc1NCCCc1cccc(c1)OCCc1cccc(c1)N2
Yield: 10.9 %

Procedure:
To a solution of 3-{3-[(2-{[3-(2-bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]propyl}phenol (50.0 mg, 0.108 mmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium hydroxide in water (1.0 mL, 1.0 M). The resultant solution was stirred at rt for 60 hours until the reaction was complete. The reaction mixture was neutralized with HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude, which was purified by silica gel column chromatography to give the desired product as a white powder (4.5 mg, 11%). LCMS for C21H22ClN4O (M+H)+: m/z=381.0. 1H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 7.92 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.40 (m, 1H), 7.06 (m, 1H), 6.97 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.62 (m, 2H), 3.60 (m, 4H), 3.20 (m, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.02 (t, J=7.6 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][C:24]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:25]4)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.Cl[CH2:40]CCl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O>[CH3:40][N:1]1[CH2:2][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=3[C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][C:24]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:31])=[O:32])=[CH:25]4)=[CH:8][CH:7]=[N:6]2)[CH2:4]1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-c3ccnn3C3CNC3)cccc2c1
Reactant: ClCCCl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4nccs4)ccc23)C1
Reaction time: 0.03 h

Procedure:
A flask was charged with 5-(2-(1-(azetidin-3-yl)-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (26.25 mg, 0.047 mmol), DCE (1 mL), AcOH (0.05 mL), and formaldehyde (37% aq.) (10.55 μl, 0.142 mmol). The mixture was stirred for 2 min, then sodium triacetoxyborohydride (20.03 mg, 0.094 mmol) was added in one portion. The resulting mixture was stirred for 3 h, then concentrated. The residue was dissolve in MeOH, and this solution was loaded onto a 500 mg SCX-2 ion exchange column (Biotage AB, Uppsala, SE). The column was eluted with methanol, then with 2N ammonia in methanol. The basic fraction was concentrated to afford 5-(2-(1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (23.53 mg, 0.041 mmol) as a beige-solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.40 (s, 1H), 8.09 (d, J=7.9 Hz, 1H), 8.00 (d, J=6.9 Hz, 1H), 7.82 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.62-7.51 (m, 2H), 7.39 (d, J=6.8 Hz, 1H), 7.29 (s, 1H), 7.15 (d, J=4.1 Hz, 1H), 6.71 (d, J=4.0 Hz, 1H), 5.99 (s, 1H), 4.59 (td, J=7.3, 14.2 Hz, 1H), 3.66-3.59 (m, 1H), 3.33 (t, J=7.0 Hz, 1H), 3.09-2.95 (m, 2H), 2.27 (s, 3H). m/z (ESI) 570.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].C(=O)=O.C(O)(C)C.C1([Mg]Br)C=CC=CC=1.[CH:28](=[O:32])[CH:29]([CH3:31])[CH3:30]>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(I)c1
Reactant: CC(C)C=O
Agent: Br[Mg]c1ccccc1
Agent: O=C=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)C(O)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.7 %

Procedure:
To a solution of 3-iodo-4-nitrobenzonitrile (314 mg, 1.14 mmol) in anhydrous tetrahydrofuran (5.5 mL) cooled at minus 45° C. (dry ice-isopropanol bath) under nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.16 mL, 6.32 mmol) was added at a rate to keep the temperature at or below minus 40° C. Upon completion of the addition the mixture was stirred for five minutes, then isobutyraldehyde (0.957 mL, 10.54 mmol) was added. The mixture was allowed to gradually warm up to room temperature, then quenched with saturated NH4Cl (2 mL) and poured into water (50 mL)/dichloromethane (50 mL). The organic layer was separated; aqueous layer was extracted three times with dichloromethane (25 mL each). Combined organic extract was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to yield racemic (RS)-1-(5-cyano-2-nitrophenyl)-2-methyl-1-propanol (57 mg, 23%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 1H, J=8.1 Hz, Ph-H), 7.74 (s, 1H, Ph-H), 7.21 (d, 1H, J=8.1 Hz, Ph-H), 4.72 (d, 1H, J=3.6 Hz, Ph-CH), 2.33 (br. s, 1H, OH), 2.03 (m, 1H, CHCH(CH3)2), 1.04 (d, 3H, J=6.8 Hz, CH3), 0.89 (d, 3H, J=6.6 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 147.78 (C), 140.25 (CH), 131.40 (CH), 131.24 (CH), 118.36 (C), 112.27 (CN), 103.82 (C), 80.80 (CH), 33.56 (CH), 19.70 (CH3), 15.62 (CH3).