Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][SH:7])[CH3:3].[OH-].[Na+].[Cl:12][CH2:13][CH2:14][N:15]([CH2:39][CH2:40][Cl:41])[P:16]([N:32]([CH2:36][CH2:37][Cl:38])[CH2:33][CH2:34][Cl:35])(=[O:31])[O:17][CH2:18][CH2:19]OS(C1C=CC(Br)=CC=1)(=O)=O>CO>[Cl:41][CH2:40][CH2:39][N:15]([CH2:14][CH2:13][Cl:12])[P:16]([N:32]([CH2:36][CH2:37][Cl:38])[CH2:33][CH2:34][Cl:35])(=[O:31])[O:17][CH2:18][CH2:19][S:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:2][CH3:3]
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: CCN(CC)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Yield: 42.4 %

Procedure:
To a solution of 2-(diethylamino)ethanethiol hydrochloride (840 g, 5 mmol) in methanol (20 mL) was added NaOH (3.8 mL of 4M solution in methanol, 15 mmol, 3 eq.) and 2-(4-bromobenzenesulfonyloxy)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate (7.0 mL of 0.7M solution in toluene, 4.9 mmol, 0.98 eq.). The mixture was stirred at room temperature until all the 2-(4-bromobenzenesulfonyloxy)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was consumed, as determined by HPLC-ELSD. The mixture was acidified to pH 7 with 1.0 M aqueous H3PO4 and concentrated under vacuum to a thick slurry. The slurry was taken up in ethyl acetate (400 mL) and washed with 5% aqueous NaHCO3 (2×400 mL) and then with aqueous HCl (2×400 mL). The acidic aqueous layers were combined and brought to pH>9 with solid NaHCO3, then extracted with ethyl acetate (2×800 mL). The ethyl acetate solution was separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 2-{[2-(diethylamino)ethyl]thio}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate as a clear oil (1.05 g, 42% yield). The 2-{[2-(diethylamino)ethyl]thio}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was oxidized to 2-{[2-(diethylamino)ethyl]sulfonyl}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate and isolated as the hydrochloride salt using the procedure of Synthetic Example 1. MS (ES+): m/z=536 [C16H35Cl4N3O4PS+H]; 1H NMR (CD3OD): δ=1.36 (t, J=7.4 Hz, 6H), 3.28-3.34 (m, 2H), 3.40-3.50 (m, 10H), 3.65-3.77 (m, 14H), 4.51 (dd, J=5.1, 6.3 Hz, 2H); 31P NMR (CD3OD): δ=18.02.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH3:26])=[C:17]([O:27][CH3:28])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[N:32]([Si](C)(C)C)[S:33]([CH3:36])(=O)=O>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:32][S:33][CH3:36])[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH3:26])=[C:17]([O:27][CH3:28])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC#CCOc1ccc(CCNC(=O)C(=O)c2ccc(Cl)c(Cl)c2)cc1OC
Reactant: C[Si](C)(C)N([Si](C)(C)C)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC#CCOc1ccc(CCNC(=O)C(=NSC)c2ccc(Cl)c(Cl)c2)cc1OC
Yield: 70.1 %

Procedure:
To a solution of 1.7 g (3.9 mmol) 2-(3,4-dichloro-phenyl)-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-2-oxo-acetamide in 32 ml THF, 3.0 g (14.0 mmol) N,N-bis(trimethyl-silyl) methanesulfonamide and 0.1 g (0.32 mmol) tetrabutylammonium bromide (TBAF) are added. The mixture is heated at +70° C. for 7 hours. After cooling, the mixture is diluted with ethyl acetate and washed twice with water. After evaporation of the organic phase the residue is purified by flash-chromatography (ethyl acetate 25, hexanes 75) to give 1.31 g (70%) of the 2-(3,4-dichloro-phenyl)-2-methylthioimino-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 1.15 (t, 3 H, CH2CH3), 2.22 (m, 2 H, CH2CH3), 2.73 (s, 3 H, SCH3), 2.83 (t, 2 H, CH2CH2) 3.59 (t, 2 H, CH2CH2) 3.89 (s, 3 H, OCH3) 4.73 (m, 2 H, OCH2) 6.78 (m, 2 H, CH arom.), 7.02 (m, 1 H, CH arom.), 7.12 (t, 1 H, NH), 7.30 and 7.58 (m, 3 H, CH arom.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Br:21])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:23](=[O:27])[CH:24]([CH3:26])[CH3:25].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Br:21])[CH:14]=1)[C:24]([CH3:26])([CH3:25])[CH:23]2[OH:27])=[O:22])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Br)cc(OC)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)cc(OC)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.3 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-methoxy-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.5 g, 12.4 mmol) and ytterbium(III) triflate hydrate (0.77 g, 1.24 mmol) in dry tetrahydrofuran (20 mL) at 25° C. was added isobutyraldehyde (0.89 g, 12.4 mmol) and water (0.22 mL, 12.4 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-methoxy-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.4 g, 100%) as a light yellow oil: LC/MS m/e calcd for C21H24BrNO4 M+: 434.3, observed: 418.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)cc1
Yield: 26.3 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and diethylamine (0.40 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N,N-diethylbenzenesulfonamide (0.12 g) was provided after purification. MS (ESI) m/z 293. HPLC purity 99.2% at 210-370 nm, 9.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.O.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][NH:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.359 g, 0.96 mmol), prepared as described in Example 2, ammonium formate (0.304 g, 4.82 mmol) and palladium (10% wt. on activated carbon, 40 mg) in MeOH (5 mL) was stirred at r.t. for one h and then at 60° C. for two h. The mixture was cooled to r.t. and filtered over celite. The filtrate was concentrated under reduced pressure to give a white solid which was dissolved in water. The mixture was extracted twice with a 3:1 mixture of chloroform:isopropanol. The combined organic extracts were dried over sodium sulfate and concentrated to dryness to give 0.26 g (96%) of the title compound which was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:4]=1[C:5]([N:7]=[C:8]=[O:9])=[O:6].[Br:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH:7][C:8]([NH:28][C:25]1[CH:26]=[N:27][C:22]([O:21][C:20]2[CH:29]=[CH:30][C:17]([Br:16])=[CH:18][CH:19]=2)=[CH:23][CH:24]=1)=[O:9])=[O:6]
Reactant: Nc1ccc(Oc2ccc(Br)cc2)nc1
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1ccc(Oc2ccc(Br)cc2)nc1

Procedure:
2,6-Dimethoxybenzoyl isocyanate (2.0 grams) and 6-(4-bromophenoxy)-3-aminopyridine (2.3 grams) were mixed in about 50 ml. of ethyl acetate at room temperature, and the reaction mixture stirred overnight (about 17 hours) at room temperature. The product was separated by filtration and crystallized from a mixture of ethyl acetate and ethanol, yield 0.9 gram, m.p., 177°-179° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:24])=O>C1COCC1.CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of compound 29d (100 mg, 0.35 mmol) in THF (2 mL) was added oxalyl dichloride (46 μL, 0.53 mmol) dropwise at 0° C., followed by addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, and was then warmed up to room temperature overnight. The solvents were removed under reduced pressure, and the residue, compound 29e, was dried under reduced pressure for 2 h and then used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]([CH3:13])([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CNC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)(C)Oc1ccc(OCc2cccc(Cl)c2)cc1

Procedure:
In analogy to the procedure described in Example 3 b), the alkylation of 2-(4-hydroxy-phenoxy)-2,N-dimethyl-propionamide with 3-chloro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the 2-[4-(3-chloro-benzyloxy)-phenoxy]-2,N-dimethyl-propionamide as an brown oil; MS: m/e=334 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:10]([OH:12])=[O:11].[CH:13]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[CH3:13][O:11][C:10]([C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:2]1[NH2:1])=[O:12]
Reactant: N[C@H]1CCCCCC[C@H]1C(=O)O
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1CCCCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
cis-2-Amino-cyclooctanecarboxylic acid (0.65 g, 3.8 mmol) was dissolved in methanol (5 mL). Benzene (7.5 mL) was added followed by dropwise addition of a 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (3.5 mL). The yellow solution was stirred at 25° C. for 45 min. The solution was concentrated in vacuo. The residue was dissolved in methanol (20 mL) and concentrated in vacuo to afford the desired product, cis-2-amino-cyclooctanecarboxylic acid methyl ester (0.66 g, 3.56 mmol, 94%), as a colorless oil. LC-MS (ESI) calcd for C10H19NO2 185.14, found 186.2 [M+H+].
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][O:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (59 mg, 59%), MS (ISP) m/z=399.3 [(M+H)+], mp 115° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-methoxy-acetic acid.