Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].N1C2C(=CC=CC=2)C=CC=1.[Cl:16][C:17]1[C:18](O)=[N:19][CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1>>[Cl:3][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[CH:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 120 °C

Procedure:
A 2 L flask with mechanical stirrer and thermocouple was charged with POCl3 (200 g, 1.30 mol). The flask was cooled in an ice bath to an internal temperature of 0-5° C. as quinoline (84 g, 0.65 mol) was added. The product of Example 2A (227 g, 1.30 mol) was added in portions, so as to maintain the reaction temperature below 10° C. The cold bath was removed, and the mixture was warmed to 120° C. for 90 minutes. The temperature was decreased to 100° C. and the reaction mixture was quenched by addition of water (500 mL) maintaining the internal temperature between 100-110° C. After complete addition, the mixture was cooled in ice to 0-5° C. for 1 hour and filtered. The filter cake was washed with cold water and dried under vacuum at 40° C. to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 8.39 (d, J=3 Hz, 1H), 9.16 (d, J=3 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[N:30]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:28][CH2:27][N:26]([C:36]([NH:35][C:31]3[N:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[O:37])[CH2:25][CH2:24]2)=[N:13][CH:14]=1
Reactant: Brc1cnc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.3 %

Procedure:
5-Bromo-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyrimidine trifluoroacetate (0.315 mmol, from Step 5), in acetonitrile (1.5 mL) was treated with phenyl pyridazin-3-ylcarbamate (75 mg, 0.35 mmol) and diisopropylethylamine (0.192 mL, 1.10 mmol) and stirred at ambient temperature for 72 h. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (0-10% ethanol (containing 11% aq NH4OH):dichloromethane) to afford the title compound (0.099 g, 67% yield) as a white foam. MS (APCI) M=466.0; 1H NMR (400 MHz, CDCl3) δ ppm 2.50 (t, J=5.56 Hz, 2H) 2.63 (t, J=5.65 Hz, 2H) 3.59-3.67 (m, 2H) 3.73 (t, J=4.39 Hz, 2H) 6.44 (s, 1H) 7.02-7.09 (m, 2H) 7.12 (d, J=7.60 Hz, 1H) 7.41 (t, J=7.90 Hz, 1H) 7.49 (dd, J=9.06, 4.58 Hz, 1H) 8.41-8.50 (m, 1H) 8.59 (s, 2H) 8.78 (br. s, 1H).
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([C:12]1[NH:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]4[N:34]=[C:35]([C@@H:38]([NH:40]C(=O)OC(C)(C)C)[CH3:39])[NH:36][CH:37]=4)=[CH:29][CH:28]=2)[CH:21]=[CH:20]3)[N:16]=1)[CH3:11])=O)(C)(C)C>O1CCOCC1.CO>[NH2:9][C@H:10]([C:12]1[NH:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:33]4[N:34]=[C:35]([C@@H:38]([NH2:40])[CH3:39])[NH:36][CH:37]=4)=[CH:31][CH:32]=2)[CH:21]=[CH:20]3)[N:16]=1)[CH3:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(-c3ccc4cc(-c5c[nH]c([C@H](C)NC(=O)OC(C)(C)C)n5)ccc4c3)cc2)c[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1nc(-c2ccc(-c3ccc4cc(-c5c[nH]c([C@H](C)N)n5)ccc4c3)cc2)c[nH]1
Reaction time: 5 h

Procedure:
A solution of 4N HCl in dioxane (10 mL) was added to tert-butyl ((1S)-1-(4-(4-(6-(2-((1S)-1-((tert-butoxycarbonyl)amino)ethyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)ethyl)carbamate (368 mg. 0.59 mmol) in MeOH (10 mL) and stirred at ambient conditions for 5 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 334 mg). LC-MS retention time 1.33 min; calcd. for C26H27N6: 423.23 m/z Found 423.17 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min and an analysis time of 3 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([S:22][CH3:23])=[C:17]([F:24])[CH:16]=1)=O.C(N(C(C)C)CC)(C)C.N12CCCN=C1CCCCC2.Cl>C(#N)C>[F:24][C:17]1[CH:16]=[C:15]([C:13]2[CH2:12][O:9][C:8](=[O:10])[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:20]=[C:19]([F:21])[C:18]=1[S:22][CH3:23]
Reactant: CSc1c(F)cc(C(=O)CBr)cc1F
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1c(F)cc(C2=C(c3ccccc3)C(=O)OC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a mixture of phenylacetic acid (4.2 g, 0.030 mol) and crude 2-bromo-1-[3,5-difluoro-4-(methylthio)-phenyl]ethanone (8.6 g, 0.030 mol) in anhydrous acetonitrile (100 mL) was added diisopropylethylamine (3.9 g, 0.030 mol). The reaction mixture was stirred for one hour at room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 g, 0.032 mol) was added. After 2 hours the mixture was poured into dilute HCl and extracted with dichloromethane (1×200 mL, 2×75 mL). The combined extracts were dried using magnesium sulfate, and concentrated. The residue was treated with anhydrous acetonitrile (100 mL) and DBU (10.0 g, 0.065 mol), stirring at room temperature for 3 hours. The mixture was poured into dilute HCl and extracted with dichloromethane (1×200 mL, 2×50 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Purification by silica gel chromatography using 5% dichloromethane/10% ethyl acetate in hexanes afforded 4-[3,5-difluoro-4-(methylthio)-phenyl]-3-phenylfuran-2(5H)-one as an orange liquid (7.2 g, 76%). 1H NMR (CDCl3/400 MHz) 7.37-7.41 (m, 5H), 6.97 (m, 2H), 5.09 (s, 2H), 2.48 (s, 3H). ESHRMS m/z 319.0601 (M+H+, Calcd 319.0604). Anal. Calcd for C17H12F2O2S: C, 64.14; H, 3.80. Found: C, 63.56; H, 3.54.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[I:25]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([I:25])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccn(-c2ccc(F)cc2)n1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(I)n(-c2ccc(F)cc2)n1
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Under argon atmosphere, a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-1H-pyrazole (599 mg) in tetrahydrofuran (4 ml) was cooled to −78° C., n-butyllithium (1.8 ml, 1.6M solution in n-hexane) was added dropwise thereto, and the mixture was stirred for 30 minutes. To this reaction solution was added dropwise a solution of iodine (715 mg) in tetrahydrofuran (2 ml), the mixture was stirred for additional 30 minutes. To this reaction mixture was added a saturated aqueous solution of sodium sulfite, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the resulting solid residue was added a mixed solvent of ethyl acetate/n-hexane (=1/5), and the mixture was stirred. A solid was collected from this suspension by filtration, dried under reduced pressure to give the titled compound (625 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]1[CH:30]=[CH:29][C:28](NC)=[CH:27][CH:26]=1.[C:33]([BH3-])#[N:34].[Na+]>O1CCCC1.C(O)(=O)C>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[S:19][C:20]([CH2:23][NH:34][CH2:33][C:28]5[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=5)=[CH:21][N:22]=4)[CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cnc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)s1
Reactant: CNc1ccncc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(C2CCc3cc(Oc4ncc(CNCc5ccncc5)s4)ccc3O2)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a suspension of 2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carbaldehyde (54 mg, 0.13 mmol) and pyridin-4-yl-methylamine (17 mg, 0.16 mmol, 1.2 eq) in tetrahydrofuran (3 ml) and acetic acid (0.5 ml) at 0° C. sodium cyanoborohydride (polymer bond, 2.19 mM/g, 137 mg, 0.30 mmol, 2.3 eq) was added and the mixture stirred at 40° C. for 16 h. The reaction mixture was filtered, the volatile components removed under reduced pressure and the remaining residue purified by reversed phase HPLC (water/acetonitrile gradient (+0.1% trifluoroacetic acid)) to give 30 mg (42%) of [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-pyridin-4-ylmethyl-amine in the form of its salt with trifluoroacetic acid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[CH3:16][O-:17].[Na+].CO>C(OCC)C>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:1](=[O:5])[C:2]([O:17][CH3:16])=[O:3])=[CH:8]1
Reactant: C[O-]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.50 mL; 17.2 mmol) was added dropwise to an ice cold solution of indole, A1, (2.00 g; 17.1 mmol) in anhydrous diethyl ether (20 mL). The resulting solution was allowed to stir on ice for 1 hour after which time a yellow slurry had formed. A freshly prepared solution of sodium methoxide in methanol (780 mg Na metal in 20 mL methanol; 34.1 mmol) was added, the reaction allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with the addition of water (30 mL) and the resulting orange solid isolated by fitration, washed with diethyl ether and recrystallised from methanol. Yield 2.94 g; 85%. mp 226–228° C. 1H NMR (500 MHz, DMSO-d6) 12.40 (br s, 1H), 8.17 (dd, J=1.5, 7.6 Hz, 1H), 7.55 (dd, J=1.5, 7.6 Hz, 1H), 7.29 (dt, j=1.5, 7.6 Hz, 1H), 7.26 (dt, J=1.5, 7.6 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH:6]([CH3:23])[CH2:7][C@H:8]3[C@H:16]4[C@@:12]([CH2:18][CH3:19])([C@@H:13]([OH:17])[CH2:14][CH2:15]4)[CH2:11][CH2:10][C@@H:9]3[C:20]=2[CH2:21][CH:22]=1.Cl.O>CO.[Cl-].[Na+].O>[CH2:18]([C@:12]12[CH2:11][CH2:10][C@@H:9]3[C@@H:20]4[C:5]([C@@H:6]([CH3:23])[CH2:7][C@H:8]3[C@@H:16]1[CH2:15][CH2:14][C@@H:13]2[OH:17])=[CH:4][C:3](=[O:2])[CH2:22][CH2:21]4)[CH3:19]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](C[C@H](C)C4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Yield: 31.4 %

Procedure:
Stir dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-2,5(10)-diene (1.0 g) in methanol (54 cc) containing concentrated hydrochloric acid (3.6 cc) and water (2.4 cc) under nitrogen for 1.5 hours. Pour into brine, extract with ether and isolate the crude product. Chromatograph on Grade I neutral alumina (50 g) and recrystallize from ether-hexane to obtain the title compound (0.30 g), m.p. 127°-130°, λ max. KBr 2.98 μ, 6.03 μ; λ max. EtOH 240 mμ (ε16,500).