Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1Cl
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-Chloro-3-nitrobenzenesulfonyl chloride (235 mg, 0.918 mmol) was treated with a 2 M solution of dimethylamine in methanol (0.55 mL, 1.10 mmol), and triethylamine (0.13 mL, 0.918 mmol) in methanol (1 mL), and the suspension was stirred at room temperature for 2.5 h. The volatiles were removed in vacuo, and the residue was purified by column chromatography using heptane/ethyl acetate, 70:30-50:50 as an eluent, affording 2-chloro-N,N-dimethyl-3-nitrobenzenesulfonamide, 202 mg (83%) as a white solid. MS (ESI) m/z 265 [M+H]. 1H NMR (400 MHz, CDCl3) δ ppm 2.95 (s, 6 H); 7.56 (t, J=8.0 Hz, 1H), 7.88 (dd, J=8.1, 1.5 Hz, 1H), 8.31 (dd, J=8.1, 1.5 Hz, 1H).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].[Cl:29][C:30]1[CH:31]=[C:32]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:33][N:34]([CH3:45])[C:35]([C:37]1[CH2:38]N(C)[C:40](=[O:43])[C:41]=1[OH:42])=[O:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:33][N:34]([CH3:45])[C:35]([C:37]1[CH2:38][N:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:40](=[O:43])[C:41]=1[OH:42])=[O:36]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: NCCC(=O)O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)O)C1
Yield: 25 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and β-alanine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber solid (48.5 mg, 25% yield). Mp=183–184° C. 1H NMR (500 MHz, DMSO) δ: 12.34 (s, 2H), 10.79 (s, 1H), 7.61 (d, 1H, J=8.54), 7.51 (s, 1H), 7.24 (bs, 1H), 4.57 (s, 2H), 4.06 (s, 2H), 3.58 (t, 2H, J=6.40), 2.96 (bs, 3H), 2.54 (t, 2H, J=7.02). HRMS (M−H) calcd for C16H15N2Cl2O5: 385.0358. found: 385.0364.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[CH3:37]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:26][C:25]=2[CH3:37])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2ccc(=O)[nH]n2)ccc1OCCN
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Product: Cc1cc(-c2ccc(=O)[nH]n2)ccc1OCCNCC(O)COc1ccc(COCCOC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(Br)cc1

Procedure:
A round bottom flask was charged with 4-bromobenzoic acid (2.0 g, 9.95 mmol) in chloroform (150 mL). To the solution was added thionyl chloride (3 mL) in chloroform (10 mL), 2-3 drops of dimethylformamide (DMF). The slurry was heated at reflux for 3 hr. while monitoring the reaction through a bubbler. A clear solution of 4-bromobenzoyl chloride was obtained, the volatiles were removed and a light yellow oil was obtained which solidified upon cooling.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[N:22]=[N:21][N:20]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2].[CH3:41][O:42][C:43](=[O:49])[C:44]([CH3:48])([CH3:47])[CH2:45]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([C:35]([F:36])([F:38])[F:37])[CH:26]=3)[N:22]([CH2:45][C:44]([C:43]([O:42][CH3:41])=[O:49])([CH3:48])[CH3:47])[NH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2]
Reactant: COC(=O)C(C)(C)CO
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nnnn2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC2=NNN(CC(C)(C)C(=O)OC)N2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 19 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(tetrazol-5-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (230 mg) is dissolved in tetrahydrofuran (3 ml), and thereto are added 3-hydroxy-2,2-dimethylpropionic acid methyl ester (58 μl), a solution (0.18 ml) of 40% diethyl azodicarboxylate in toluene and triphenylphosphine (121 mg). The mixture is stirred at room temperature for 19 hours, and partitioned by adding water and diethyl ether. The organic layer is washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[2-(2-methoxycarbonyl-2-methylpropyl)-2H-tetrazol-5-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (243 mg). MS (m/z): 688 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]=[C:16]2[NH2:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:27][CH:28]=O.O>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]3[CH:27]=[CH:28][N:25]=[C:16]23)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: Cc1ccnc2c1nc(N)n2-c1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccnc2c1n1ccnc1n2-c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 3-[4-(benzyloxy)phenyl]-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine (4.96 g) and 6.1 M aqueous chloroacetoaldehyde solution (4.92 ml) in DMA (50 ml) was stirred at 100° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from hexane/THF to give the title compound (1.39 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:12]=2)[CH:7]=[CH:8][C:9]=1[F:10].C(N(CC)CC)C.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[F:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[CH:12]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:14]=[C:15]([O:17][CH3:18])[N:16]=2)=[CH:5][C:4]=1[CH2:3][NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(CN)c3)nc(OC)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)NCc1cc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)ccc1F
Reaction time: 15 h

Procedure:
A solution of [6-(3-aminomethyl-4-fluoro-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [200 mg, 0.52 mmol, see example 27] and triethylamine (264 mg, 2.61 mmol) in DCM (5 mL) is treated with methoxyacetyl chloride (114 mg, 1.1 mmol) at 0° C. After 15 hours at 4° C. in a refrigerator, the mixture is quenched with water (10 mL) filtered through Chem-Elut. The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 10% MeOH in DCM to give N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-2-methoxy-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-(2-Fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-2-methoxy-acetamide hydrochloride [190 mg, 74%, Example 28]. LCMS: RT=2.35 minutes, MS: 455 (M+H). IC50=9 nM
Reaction SMILES: CS[CH:3]([S:8][CH3:9])[CH2:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>O1CCOCC1>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:22][N:21]([CH3:23])[CH2:20][C:18]1[O:19][C:15]([CH2:14][S:13][CH2:12][CH2:11][NH:10][C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:16][CH:17]=1
Reactant: CSC(C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 99.4 %

Procedure:
A solution of 1,1-bis(methylthio)-2-nitroethane (19.8 g) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (6.42 g) in dry dioxan (120 ml) was heated at 80° C. for 6 hours. Oxalic acid (3.8 g) in dry dioxan (40 ml) was added and the crystalline solid which separated was filtered, washed with dioxan and dried to give the title compound (12.55 g) m.p. 140°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[F:45])=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH:20]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[C:21]([O:23]C)=[O:22])=[O:18])[CH:13]=2)[CH:7]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[F:45])=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH:20]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:21]([OH:23])=[O:22])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)O)C(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred solution of dimethyl 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate (75 mg, 0.12 mmol) in 10 ml of MeOH was added 2 ml of 1M NaOH. The mixture was heated at 60° C. for one hour, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioic acid as off-white solid. Yield: 72 mg, 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][C@:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][C:29](=[O:31])[CH3:30])[CH2:19][O:18]1>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][CH2:19][C@:17]([OH:18])([CH3:16])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:29](=[O:31])[CH3:30])[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(=O)Nc1ccccc1OC[C@@]1(C)CO1
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccccc1OC[C@](C)(O)CNC1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 105.6 %

Procedure:
1-(4-chlorobenzyl)-4-piperidinamine (62 mg, 0.276 mmol) and N-(2-{[(2R)-2-methyloxiranyl]methoxy}phenyl)acetamide (61 mg, 0.276 mmol) in ethanol (1.5 ml) was stirred in a sealed vial at 80° C. for 4 hours. The reaction mixture was diluted with water and purified by reversed phase HPLC to give 130 mg (70%) of the title compound as a ditrifluoroacetate after lyophilisation. The optical purity was determined to 86% ee, by chiral HPLC on a Chiralpak AD-column.