Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34]CC4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:39](N)([CH3:41])[CH3:40]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH:39]([CH3:41])[CH3:40])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Reactant: CC(C)N
Product: CC(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using isopropylamine instead of cyclopropylmethylamine. LC-MS: (M+1=517, obsd.=517).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[CH3:40][O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH3:40][O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH:46]=[N:45]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCOC)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Yield: 19.6 %

Procedure:
A mixture of diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (10.0 mg, 0.0159 mmol), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.02 mg, 0.0318 mmol), potassium carbonate (6.60 mg, 0.0477 mmol), 1,4-dioxane (0.4 mL), H2O (0.1 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.30 mg, 0.00159 mmol) was evacuated and purged with N2. The mixture was irradiated in a microwave reactor at 100° C. for 30 minutes. The crude mixture was passed through a Thiol-SPE column to remove Pd and purified by MDP to obtain the title compound (2.1 mg, 19.6% yield). 1H NMR (400 MHz, CD3OD) δ=1.25 (t, J=7.1 Hz, 6 H), 3.21 (s, 3 H), 3.30 (d, J=22.7 Hz), 3.35 (s, 3 H), 3.79 (t, J=5.2 Hz, 2 H), 4.01-4.13 (m, 4 H), 4.37 (t, J=5.2 Hz, 2 H), 4.60 (s, 2 H), 7.37 (dd, J=8.6, 2.3 Hz, 2 H), 7.57 (d, J=8.6 Hz, 2 H), 7.72 (d, J=8.8 Hz, 1 H), 7.94 (s, 1 H), 8.08 (s, 1 H), 8.36 (s, 1 H), 8.68 (br. s., 1 H). MS (ES+): m/z 674.34 (100) [MH+]; HPLC: tR=1.05 min (UPLC, purity).
Reaction SMILES: [CH3:1][C@:2]1([CH2:24][NH:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[N+:34]([O-])=O)[C:29]#[N:30])[CH2:23][CH2:22][CH2:21][C:4]2([O:8][C@H:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@@H:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:5]2)[CH2:3]1.CO.[CH:39](OC)(OC)OC.C(O)=O>[Fe].CCOC(C)=O>[CH3:1][C@:2]1([CH2:24][N:25]2[C:26]3[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:33]=3[N:34]=[CH:39]2)[CH2:23][CH2:22][CH2:21][C:4]2([O:8][C@H:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@@H:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:5]2)[CH2:3]1
Reactant: COC(OC)OC
Reactant: C[C@]1(CNc2cc(C#N)ccc2[N+](=O)[O-])CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CO
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Temperature: 64 °C
Yield: 100 %

Procedure:
A 5 L three neck flask was fitted with a mechanical stirrer and condenser. To the flask was added 3-({[(2R,3R,7S)-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}amino)-4-nitrobenzonitrile (245.5 g, 508 mmol), MeOH (891 mL) and EtOAc (891 mL). Next, trimethyl orthoformate (561 mL, 5077 mmol) and formic acid (195 mL, 5077 mmol) were added. The resulting mixture was heated at 64° C. Next, (2-3 eq) of formic acid, trimethylorthoformate and iron were added every 15 min until the reaction was finished (3.5 h). Next, the mixture was filtered to remove excess iron, and the iron was washed with EtOAc. The filtrate was concentrated and the resulting thick purple residue (residue contained formic acid) was used without further purification (235 g, 100% yield).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]2[NH:18][C:19]([S:21][CH2:22][C:23]3[N:28]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:25][N:24]=3)=[N:20][C:16]=2[CH:15]=1.N>ClCCl>[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]2[NH:18][C:19]([S:21]([CH2:22][C:23]3[N:28]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:25][N:24]=3)=[O:9])=[N:20][C:16]=2[CH:15]=1
Reactant: COc1ccc2[nH]c(SCc3nccc(N4CCCCC4)n3)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(N4CCCCC4)n3)nc2c1
Yield: 90.2 %

Procedure:
A solution of m-chloroperbenzoic acid (1.69 g) in dichloromethane (25 ml) was added to a stirred solution of 5-methoxy-2-[4-piperidino-2-pyrimidinylmethylthio]-(1H) benzimidazole (3.48 g) in dichloromethane (75 ml) cooled to between -30° and -35°. After 1.5 hours at -20° a further quantity of m-chloroperbenzoic acid (0.34 g) was added. After a further 30 minutes ammonia was passed through the reaction mixture and the precipitated solid filtered off. The filtrate was washed with aqueous sodium carbonate, which was back washed with chloroform. The combined organic phases were dried (K2CO3) stripped and the residue purified by column chromatography (silica gel, 2% MeOH-NH3 /CHCl3) to give 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole (3.28 g) as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(C)(C)C.[H-].[C:13]([CH:17]1[CH2:20][C:19](=[O:21])[CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([C@@H:17]1[CH2:20][C@H:19]([OH:21])[CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C1CC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cool lithium aluminum hydride (16 mL, 16 mmol, 1.0 M solution in tetrahydrofuran) under a nitrogen atmosphere to 0° C. Add tert-butanol (4.6 mL, 48.1 mmol) dropwise, warm to room temperature, and stir the resulting solution for 1 hour. Cool the hydride solution to −78° C. and add a solution of 3-tert-butylcyclobutanone (1 g, 7.9 mmol) in dry tetrahydrofuran (3 mL) dropwise. Stir for 1 hour at −78° C. and then warm to room temperature over 1 hour. Slowly quench the mixture with 0.1 N hydrochloric acid. Dilute the resulting mixture with ethyl acetate and a saturated aqueous solution of sodium potassium tartrate (Rochelle salt) and stir the biphasic mixture overnight. Filter the mixture to remove precipitates and separate the aqueous layer. Saturate the aqueous phase with sodium chloride and extract with ethyl acetate. Add the organic extract to the ethyl acetate solution of the reaction mixture and wash the resultant mixture with saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter, and concentrate to give the title compound as a 9:1 mixture of cis/trans diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.CS(C)=O.[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21].[ClH:29]>O>[ClH:1].[ClH:29].[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccc(Cl)nc2)cc1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2ccc(N3CCN(C(C)C)CC3)nc2)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of 2-chloro-5-(4-methoxyphenyl)pyridine (200 mg, 0.91 mmol), dry DMSO (2.0 mL) and 1-isopropylpiperazine (500 mg, 3.9 mmol) was stirred and heated on a 130° C. oil-bath overnight, then at 150° C. for 4 h, left 2 days at rt and finally heated at 140° C. overnight. The reaction mixture was allowed to cool and then poured into water (100 mL). The mixture was extracted with ethyl acetate (100 mL), and the organic extract was washed with water and dried (MgSO4). The solvent was evaporated to give a solid residue which was dissolved into 0.5 N hydrochloric acid (20 mL). A small insoluble solid was removed by filtration, and the aqueous solution was evaporated to give a residue which was re-evaporated with absolute ethanol. The resulting solid was re-crystallised from absolute ethanol to give 210 mg (60%) of 1-[5-(4-methoxyphenyl)pyridin-2-yl]-4-isopropylpiperazine, dihydrochloride.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[CH3:20][O:21][C:22]1[C:26](OC)=[N:25][S:24](=[O:29])[N:23]=1>CO>[CH3:20][O:21][C:22]1[C:26]([NH:16][CH2:15][CH2:14][S:13][CH2:12][C:10]2[N:11]=[C:7]([NH:6][C:5]([NH2:17])=[N:4][CH2:3][C:2]([F:1])([F:18])[F:19])[S:8][CH:9]=2)=[N:25][S:24](=[O:29])[N:23]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: COC1=NS(=O)N=C1NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
A solution of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole (European Patent Publication No. 30092, Example 2; 2.1 g.) in methanol (20 ml.) was added dropwise to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (UK Patent Application No. 2067987, Example 4; 1.1 g.) in methanol (50 ml.) at 5°. The solution was stirred for 1.5 hours at 5°-10°. The intermediate 3-methoxy-4-[2-(2-[2,2,2-trifluoroethyl]-guanidino)thiazol-4-ylmethylthio]ethylamino-1,2,5-thiadiazole 1-oxide was not isolated, but anhydrous ammonia in methanol (6M, 20 ml.) was added. The solution was stirred for 17 hours at 25° and the solvent was evaporated. The residue was purified by chromatography on silica gel using dichloromethane/methanol 9:1 v/v as eluant. The purified product was obtained as an oil which was dissolved in acetone and the solution was treated with an excess of maleic acid in acetone. The salt which precipitated was recrystallized from ethyl acetate/ethanol to give 3-amino-4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]ethylamino-1,2,5-thiadiazole 1-oxide maleate (2.0 g.), m.p. 113° (decomp.) having the following n.m.r. spectrum in d6 dimethylsulphoxide: 2.8 (t, 2H); 3.55 (t, 2H); 3.7 (s, 2H); 4.15 (q, 2H); 6.2 (s, 2H); 6.8 (s, 1H).
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][C:7]1=[O:17].[N:18]([O-])=[O:19].[Na+].CO>O.C(OCC)(=O)C>[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8](=[N:18][OH:19])[C:7]1=[O:17]
Reactant: Cn1c(=O)cc(O)c2ccccc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CN1C(=O)C(=NO)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Glacial acetic acid (2.7 ml) was added with stirring to a solution of 1-methyl-4-hydroxy-2(1H)-quinolinone (1.75 gm) and sodium nitrite (0.8 gm) in a solvent mixture consisting of methanol (17.5 ml), ethyl acetate (20 ml) and water (10 ml) under nitrogen atmosphere. The reaction mixture was stirred for 1.5 hrs at room temperature and the organic solvents were then removed under reduced pressure. The resulting suspension was filtered and the solid washed with water to give the title compound. That the expected product was obtained was confirmed by the spectral data: MS: m/e 204 (M+); NMR (DMSO): δ3.44(s, 3H, CH3 --N), 15.34(br, 1H, =NOH) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[N:5]2.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:12])[CH:6]=[N:5]2
Reactant: CCOC(=O)CBr
Reactant: O=c1cnc2cc(Br)ccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)cnc2cc(Br)ccc21
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Under a nitrogen atmosphere 6-bromoquinoxalin-2(1H)-one (2.03 g, 9 mmol) (J.Med.Chem., 24, (1981), 93) was dissolved in 22 ml of dry DMF and sodium hydride (0.44 g, 10.8 mmol (60% mineral oil dispersion)) was added. After stirring for 2 h, ethyl bromoacetate (1.25 ml, 11.3 mmol) was added and the mixture was stirred for 3.5 h. The reaction mixture was poured onto crushed ice and acidified (pH=4.5) by addition of dilute hydrochloric acid. The precipitate was filtered off, washed with water and air dried. The crude product (containing a minor fraction of O-alkylated product) was triturated with ether (100 ml), the precipitate filtered off, washed with ether and dried to afford 1.95 g (80%) of pure 6-bromo-1-ethoxycarbonylmethylquinoxalin-2(1H)-one. 1H-NMR (DMSO-d6):δ1.22 (t, 3H), 4.17 (q, 2H), 5.08 (s, 2H), 7.56 (d, 1H), 7.83 (dd, 1H), 8.09 (dd, 1H), 8.37 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[C:33]([F:34])=[C:32]([CH2:35][CH3:36])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[C:33]([F:34])=[C:32]([CH2:35][CH3:36])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: CCc1ccnc(C(=O)CBr)c1F
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-ethyl-3-fluoropyridine*.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[N:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]2[CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:16])[CH:12]=[CH:11][CH:10]=1>>[ClH:8].[ClH:1].[Cl:8][C:9]1[N:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:16])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cl)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cccc(Cl)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 91 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(6-chloropicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (90.5 mg, 0.209 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure, yielding 77.3 mg (91%) of the title compound. LC-MS: RT=2.86 min, [M+H]+=333.5.