Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>C1COCC1>[O:18]=[C:17]1[NH:1][C:2]2=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=[CH:8][CH:9]=[C:10]2[O:11]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2oc(=O)[nH]c12
Temperature: 80 °C
Yield: 37.2 %

Procedure:
2-amino-3-hydroxybenzoic acid (1.2 g, 7.8 mmol) was suspended in 20 ml of THF and at 0° C. CDI (1.9 g, 1.5 equiv.) was added. The mixture was warmed at 80° C. for 5 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from EtOAc/ether gave 520 mg of an orange solid. Yield=37% 1HNMR (DMSO, 200 MHz) δ 7.45 (3H, m), 10.40 (1H, bs), 12.00 (1H, bs)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Cl:1])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Product: Nc1ccc(Oc2ccc(C=O)cc2Cl)cc1[N+](=O)[O-]

Procedure:
4-[(4-Amino-3-nitrophenyl)oxy]-3-chlorobenzaldehyde was prepared from 3-chloro-4-fluorobenzaldehyde (and 4-amino-3-nitrophenol using the procedure of method 5 step 1. (M-1) 291.1, 2.59 min (LC/MS method A)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH3:12])[N:3]=1.[F:13][C@@H:14]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16](N2C=CC(=O)NC2=O)[CH2:15]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:16]2[O:17][C@H:18]([CH2:19][OH:20])[C@@H:14]([F:13])[CH2:15]2)=[C:4]([NH:11][CH3:12])[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CNc1nc(N)nc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNc1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 48 h
Yield: 56.4 %

Procedure:
2-Amino-6-methylamino-9H-purine (0.43 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 40 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added and the suspension was stirred at 45° C. After 2 days, 100 m, MeOH was added to the reaction mixture. The resulting mixture was applied to a column containing AG1-X2 (OH- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:methanol (96:4). Solvent was removed and lyophilization yielded 0.35 g of 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-methylamino-9H-purine (56%): mp 111° C.; TLC RfO. (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -30.0 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 280 (13.2); at pH 13, 280 (13.2); 1H NMR (300 MHz, DMSO-d6) δ7.91 (s, 1H, H8), 7.30 (b, 1H, NH), 6.22 (dd, 1H, H1', J=9.4 Hz, J=5.5 Hz), 5.85 (bs, 2H, NH2), 5.55 (t, 1H, OH5', J=5.3 Hz), 5.40 (dd, 1H, H3', J=53.7 Hz, J=4.0 Hz), 4.19 (dm, 1H, H4', J=27.5 Hz), 3.59 (t, 2H, H5' and H5", J=4.6 Hz), 2.82-2.96 and 2.50-2.61 (m, 5H, NCH3, H2' and 2"); MS (ci) 283 (M+1), 263 (M-F), 165 (MH2 --C5H8FO2).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1)=[N:6]2
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Nc2ncc3c(C)nc(-c4cccc(C(F)(F)F)c4)n3n2)c1
Yield: 28.7 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), N-(3-bromophenyl)acetamide (0.018 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave N-[3-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)phenyl]acetamide (0.011 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.94 (s, 1H), 9.87 (s, 1H), 9.31 (s, 1H), 8.81 (s, 1H), 8.71 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.83-7.72 (m, 2H), 7.59-7.54 (m, 1H), 7.28-7.20 (m, 2H), 2.56 (s, 3H), 2.04 (s, 3H). MS m/z 427 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[S:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:30]2[CH2:31][CH2:32][S:27][CH2:28][CH2:29]2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: OC1CCSCC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCSCC2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-2H-thiopyran-4-ol in analogy to Example 9c): MS (ISP): 496.2 and 498.1 (M+H)+, 396.1 and 397.9 ((M-Boc)+H)+ (100%).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[NH:20][CH:19]=1)=O)=O)C1C=CC=CC=1.C(Cl)Cl.CO.[OH-].[NH4+]>>[CH2:35]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH3:9])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(c1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12

Procedure:
(R)-3 -(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-dibenzylamino-1H-indole was used. Column chromatography using solution with methylene chloride/methanol/ammonium hydroxide [9:1:0.1] afforded the title compound as a pale green foam: 1H NMR (CDCl3) δ7.82 (br s, NH), 7.35-7.19 (m, 10H), 7.20 (d, J=8.6 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 6.85 (dd, J=2.3 and 8.7 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 4.65 (s, 4H), 3.25-3.02 (m, 2H), 2.52 (dd, J=9.5 and 13.9 Hz, 1H), 2.39-2.15 (m, 2H), 2.30 (s, 3H), 1.85-1.40 (m, 4H); 13C NMR (CDCl3) δ143.2, 139.7, 130.5, 128.5, 128.2, 127.3, 126.8, 122.9, 112.5, 112.2, 111.8, 103.4, 67.0, 57.4, 56.4, 40.6, 31.4, 29.7, 21.9. HRMS: calculated for C28H31N3 409.2520. Found 409.2475.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.CCN(CC)CC.[CH2:17]([NH2:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CCC>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:25][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]=1[NH2:1]
Reactant: NCCc1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1NCCc1ccccc1
Reaction time: 12 h

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in nBuOH was treated with Et3N (1.2 mmol) and phenethylamine (1.05 mmol) at 80° C. After 12 h, the cooled reaction mixture was evaporated under vacuum and the residue was chromatographed to give 6-chloro-5-amino-4-(phenethylamino)-pyrimidine as a yellow solid. mp 156-157° C.; TLC: Rf=0.41, 50% EtOAc-hexane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([CH3:19])[CH:12]=1)[CH:8]=[CH2:9].[Cl-].[NH4+].Cl>O1CCCC1>[CH2:7]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[C:13]([CH3:19])[CH:12]=1)[CH:8]=[CH2:9]
Reactant: C=CCOc1ccc(C=O)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCOc1ccc(CO)c(C)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
8.50 g (224 mmol) lithium aluminium hydride were given to 250 ml Tetrahydrofuran (THF) and stirred for 20 min. A solution of 19.4 g (110 mmol) 4-allyloxy-2-methyl-benzaldehyde in 100 ml THF was added dropwise and stirring continued for 3 h. The reaction mixture was cooled to 0° C., carefully hydrolysed with 40 ml concentrated ammonium chloride solution, stirred for 60 min. and adjusted to pH=5 with conc. hydrochloric acid. A formed salt precipitate was removed by filtration, washed with THF and the combined organic solutions evaporated. Chromatography of the residue on silica (n-heptane/ethyl acetate 1:3) gave 16.0 g (81%) (4-allyloxy-2-methyl-phenyl)-methanol as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]Br.S(=O)(=O)(O)O>>[Br:10][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1]
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: BrBr
Agent: O=S(=O)(O)O
Product: Cc1ncc(F)c(Cl)c1Br

Procedure:
4-Chloro-5-fluoro-2-picoline, the product of Example 66, is treated with bromine in fuming sulfuric acid containing 65% sulfur trioxide for 7 hours at 80° C. as described by L. van der Does and H. J. Hertog in Rec Trav Chim 81: 864 (1965) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C)C(=O)C>[C:26]([O:25][C:23](=[O:24])[CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (10 g), N,N-dimethylacetamide (100 ml), potassium carbonate (17.8 g) and t-butyl bromoacetate (9.9 ml) were mixed, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was filtered through celite. Water and ethyl ether were added to the filtrate, and the mixture was partitioned in a separatory funnel. The aqueous layer was extracted with ethyl ether, and the organic layers were combined. The organic layer was washed 3 times with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was stirred. This slurry was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (12.23 g, 77%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12]CC(O)=O>ClCCl>[CH3:7][O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CCCCC(=O)O
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of oxalyl chloride (0.040 mole) in dichloromethane (20 mL) is added dropwise to an ice bath cooled solution of adipic acid monomethyl ester (Aldrich) (0.040 mole) in dichloromethane (50 mL). The reaction is stirred at ambient temperature for 5 hours. The reaction solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give 6-methoxy-6-oxohexanoyl chloride. See Musso, et. al., J. Med. Chem., (2003) 46:409.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:9]1([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:10][CH2:11]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1
Reactant: OC1(COC2CCCCO2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OC1(COC2CCCCO2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol (1.6 g, 9.3 mmol) and benzoic acid (1.25 g, 11.16 mmol, Shanghai Haiqu chemical Ltd.) in 50 mL of CH2Cl2 was added DMAP (227 mg, 1.86 mmol, Shanghai Haiqu chemical Ltd.) and EDCI (2.73 g, 14.25 mmol, Shanghai Haiqu chemical Ltd.) at rt. The reaction mixture was stirred at rt overnight, then concentrated and purified by a silica gel column chromatography (20:1 (v/v) petroleum ether/EtOAc)) to afford the title compound as colorless oil (1.8 g, 70%).