Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].CNCCNC.O>CS(C)=O>[CH3:8][C:6]1[C:5]([NH2:9])=[CH:4][CH:3]=[C:2]([S:11]([CH3:10])(=[O:13])=[O:12])[N:7]=1
Reactant: Cc1nc(Br)ccc1N
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(S(C)(=O)=O)ccc1N
Temperature: 150 °C
Yield: 60.2 %

Procedure:
A mixture of 6-bromo-2-methylpyridin-3-amine (40.0 g, 214 mmol), sodium methanesulfinate (87.3 g, 855 mmol), copper(I)trifluoromethanesulfonate-benzene complex (10.8 g, 21.4 mmol), and N1,N2-dimethylethane-1,2-diamine(10.8 g, 21.4 mmol) in DMSO (300 mL) was heated at 150° C. for four hours, cooled, and H2O (100 mL) was added. The dark brown solution was extracted with ethyl acetate (6×30 mL). The organic layer was washed with H2O (100 mL) to remove DMSO. The aqueous layer was back extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. After the volume of the filtrate was reduced to about 200 mL under reduced pressure, a solid product was precipitated and collected by filtration to give the title compound (24.0 g, 60%) as a brown powder. Exact mass calculated for C7H10N2O2S: 186.1. Found: LCMS m/z=187.1 (M+H+); 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 3.13 (s, 3H), 4.66 (bs, 2H), 7.01 (d, J=8.34 Hz, 1H), 7.71 (d, J=8.34 Hz, 1H).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.Cl>O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(NCCCOc2cccc3ccccc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCOc2cccc3ccccc23)cc1

Procedure:
A solution of 6 g. of ethyl 4-[3-(1-naphthyloxy)propylamino]benzoate and 3.4 g. of 85% KOH in 75 ml. 95% ethanol is heated at 80° C. for 4 hours, the reaction then diluted with 150 ml. of water and adjusted to pH 3 with 37% HCl. The resulting oily solid is extracted using several portions of warm ether. The extracts are combined, dried, and evaporated to a solid which is crystallized from acetonitrile to yield crystals, m.p. 146°-147° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][SH:8])[C:4](Br)=[CH:3][CH:2]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+].[OH-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCCC1.CCCCCC>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=3[CH2:7][S:8]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: SCc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)SCc1ccccc12
Reaction time: 6 h

Procedure:
81.0 g (0.40 mole) of 2-bromobenzylthiol were dissolved in 800 ml of tetrahydrofuran, and 516 ml of a solution containing 0.84 mole of butyllithium (as a 1.6 M solution in hexane) were added dropwise thereto over a period of 6 hours at a temperature of −78° C. The mixture was then stirred for 1.5 hours at the same temperature, after which 800 ml of a tetrahydrofuran solution containing 79.5 g (0.40 mole) of 1-t-butoxycarbonyl-4-piperidone was added dropwise thereto over a period of 3 hours. The solution was then stirred for a further 1 hour, and then a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. 2 liters of 4 N aqueous sulfuric acid were added to the residue, and then the mixture was heated under reflux for 14 hours. At the end of this time, the solution was made basic by the addition of 350 g (8.75 mole) of sodium hydroxide, whilst ice-cooling, and then 102 g (0.47 mole) of di-t-butyl dicarbonate were added thereto. The mixture was then stirred for 1 hour. At the end of this time, the product was extracted with methylene chloride, and the organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 97:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 56 g of the title compound as white crystals, melting at 131.0-132.5° C. (after crystallisation from hexane/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=4)=[CH:19][C:12]=3[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C(Cl)(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=4)=[CH:19][C:12]=3[N:11]=2)=[CH:3][C:2]=1[N:1]1[CH2:32][CH2:33][CH2:34][C:35]1=[O:36]
Reactant: O=C(Cl)CCCCl
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2ccc(Cl)c(N)c2)n3C)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2ccc(Cl)c(N4CCCC4=O)c2)n3C)ccn1
Reaction time: 2 h

Procedure:
To (4-{2-[(3-amino-4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide in chloroform was added 4-chlorobutanoylchloride (1.5 eq) and sodium phosphate (3 eq) and stir for 2 hours. Acylation was checked by HPLC/MS. The mixture was partitioned between methylene chloride and water. The organic layer was dried with sodium sulfate and concentrated. The crude was taken in tetrahydrofuran and Potassiumbis(trimethylsilyl)amide (2 eq) was added to it and the mixture was heated at 100 C for 16 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was dried and concentrated to give 4-[(2-{[4-chloro-3-(2-oxopyrrolidin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([NH2:14])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:14][CH2:12][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCN(Cc2ccccc2)CC1
Yield: 65.3 %

Procedure:
A suspension of 1-benzylisonipecotamide (9.0 g, 41.2 mmol) in 300 mL THF was treated portionwise with LAH (3.13 g, 82.4 mmol). The mixture was heated at reflux overnight. Upon cooling the excess LAH was decomposed by the stepwise addition of 3.13 mL H2O, 3.13 mL 1N NaOH, 9.5 mL H2O and 36 g Na2SO4. The solids were filtered and washed with ethyl acetate. The combined filtrates were concentrated in vacuo to give 5.5 g of the product as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=4)[N:9]=3)[N:7]=2)[CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)n3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)c1

Procedure:
The title compound was prepared from 2-(6-bromo-pyridin-2-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.100) (0.600 g, 1.34 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.448 g, 1.74 mmol) according to the general procedure VI. Obtained as a light yellow foam (0.318 g, 41%). MS (ISP) 581.6 [(M+H)+]; mp 75° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[NH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]1>CN1CCCC1=O>[NH2:23][C:20]1[N:19]=[C:18]([CH3:24])[C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([N:29]4[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]4)[N:3]3[CH2:25][CH:26]3[CH2:28][CH2:27]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: OCC1CCNCC1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(CO)CC3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and 4-piperidinemethanol (172 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 0.5 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give {1-[(2-(2-amino-4-methylpyrimidin-5-yl)-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-yl}methanol (69 mg, 58%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[C-:12]#[N:13].[Na+].C(Cl)Cl.C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:12]#[N:13])[CH:5]=[N:4][C:3]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1ncc(CBr)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ncc(CC#N)cc1Br
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 3-bromo-5-bromomethyl-2-methoxy-pyridine (Step AM2) (3.9 g, 14.0 mmol) in H2O was added NaCN (750 mg, 15.3 mmol) and the mixture was stirred at 50° C. for 1.5 h. CH2Cl2 and a saturated aqueous solution of NaHCO3 were added and the phases were separated. The organic layer was washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (heptane/EtOAc, 80:20→0:100). tR: 0.88 min (LC-MS 1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:17]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:11]=3)[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COC(=O)/C=C/c1ccncc1N=C=Nc1cccc(C(F)(F)F)c1
Product: COC(=O)CC1c2ccncc2N=C(N2CCN(c3cccc(Cl)c3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 250 mg (0.34 mmol) of the carbodiimide from Example 17A and 71 mg (0.36 mmol) of 3-chlorophenylpiperazine, general procedure [C] and purification by preparative HPLC result in 102 mg (53% of theory) of product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([N:16]=[N+:17]=[N-:18])[C@H:10]([OH:11])[CH2:9][C@@H:8]2[C@H:6]1[C@H:7]2[C:12]([O:14][CH3:15])=[O:13])=[O:4].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@:5]1([N:16]=[N+:17]=[N-:18])[C:10](=[O:11])[CH2:9][C@@H:8]2[C@H:6]1[C@H:7]2[C:12]([O:14][CH3:15])=[O:13])=[O:4]
Reactant: COC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OC)[C@@H]21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1[C@@H]2CC(=O)[C@@](N=[N+]=[N-])(C(=O)OC)[C@@H]21
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid dimethyl ester (XII) (239 mg, 0.94 mmol) in DCM (6 mL) was added PCC (1.13 g, 2.62 mmol, 50% on silica gel) at 0° C. and the mixture was stirred at 23° C. for 2 d. The PCC was removed by filtration through a silica gel column and the pure (1S,2R,5R,6S)-2-azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic dimethyl ester (XIII) was obtained by silica gel column chromatography with hexane/EtOAc 2:1 as a white solid (152 mg, 64%). 1H-NMR (250 MHz, CDCl3) □1.64 (1H, t,J=3.4 Hz), 2.34 (1H, ddd,J=7.7, 5.5, 3.2 Hz), 2.46 (1H, dd,J=7.7, 3.1 Hz), 2.56 (1H, d,J=19.2 Hz), 3.06 (1H, dd, J=19.2, 5.5 Hz), 3.71 (3H, s), 3.89 (3H, s); MS[EI] 222 [(M-OCH3)+ ]; mp 62-65° C.;
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14][CH3:15])=[N:4][CH:5]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:3]([S:14][CH3:15])=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1
Reactant: CSc1ncc(C#C[Si](C)(C)C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(SC)c(Cl)c1
Reaction time: 8 h
Yield: 98.8 %

Procedure:
3-Chloro-2-methylthio-5-(trimethylsilylethynyl)-pyridine (1.1 g, 4.3 mmol) was dissolved with stirring in methanol (50 mL) and anhydrous potassium carbonate (2.5 g, 0.018 mol) added. The mixture was stirred overnight, filtered, and evaporated to dryness. The residue was slurried in dichloromethane (100 mL), filtered, and evaporated to dryness. The residue was purified by chromatography over silica (0-3% ethyl acetate:hexane) to give the desired product (0.78 g, 95%) as a pale solid which darkens on standing, melting point. 58-60° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:45]1[CH:46]=[CH:47][C:48](/[C:53](/[C:72]2[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=2)=[CH:54]/[C@@H:55]2[N:59]([CH2:60][C:61]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=3[O:69][CH3:70])[C:58](=[O:71])[CH2:57][CH2:56]2)=[N:49][C:50]=1[O:51][CH3:52]>O1CCOCC1.C(OCC)(=O)C.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].O>[Cl:78][C:75]1[CH:74]=[CH:73][C:72](/[C:53](/[C:48]2[CH:47]=[CH:46][C:45]([C:9]3[CH:13]=[N:12][NH:11][CH:10]=3)=[C:50]([O:51][CH3:52])[N:49]=2)=[CH:54]\[C@@H:55]2[N:59]([CH2:60][C:61]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=3[O:69][CH3:70])[C:58](=[O:71])[CH2:57][CH2:56]2)=[CH:77][CH:76]=1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(Cl)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(Cl)cc2)c2ccc(-c3cn[nH]c3)c(OC)n2)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (216 mg), tris(dibenzylideneacetone)dipalladium(0) (33.7 mg), tri(2-furyl)phosphine (51.5 mg) and cesium carbonate (239 mg) were added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-chlorophenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-43 (200 mg) in 1,4-dioxane (3 mL)-water (1 mL), and the mixture was stirred at an external temperature for 80° C. for three hours. The reaction solution was left to cool, diluted with ethyl acetate and filtered through celite. The filtrate was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to give (5R)-5-{(E)-2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (125 mg, 63%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].S([O-])([O-])(=O)=O.CS[C:12]([NH2:24])=[NH+:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[CH3:23].CS[C:27]([NH2:39])=[NH+:28][CH2:29][CH2:30][S:31][CH2:32][C:33]1[N:34]=[CH:35][NH:36][C:37]=1[CH3:38]>>[CH3:38][C:37]1[NH:36][CH:35]=[N:34][C:33]=1[CH2:32][S:31][CH2:30][CH2:29][N:28]=[C:27]([NH2:39])[NH:1][CH2:2][CH2:3][NH:4][C:12]([NH2:24])=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[CH3:23]
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Reactant: NCCN
Agent: O=S(=O)([O-])[O-]
Product: Cc1[nH]cnc1CSCCN=C(N)NCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
The reaction of 1,2-diaminoethane (0.60 g) with S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (5.86 g) by the method described in Example 5 afforded the title compound which was isolated as the dipicrate (3.5 g), m.p. 201-203°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reaction time: 18 h

Procedure:
11.28 g benzyl 4-(4-nitro-phenyl)-piperazine-1-carboxylate are dissolved in 500 mL MeOH and combined with 1 g Raney nickel. The mixture is hydrogenated for 18 h at 5 bar H2 pressure. Then the mixture is filtered to remove the catalyst, 70 mL of 1 N aqueous hydrochloric acid are added and the solvent is eliminated in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13](C(O)=O)[C:14]([OH:16])=[O:15])[CH3:2].C(=O)=O>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1ccc2[nH]cc(CC(C(=O)O)C(=O)O)c2c1
Agent: O=C=O
Product: CCc1ccc2[nH]cc(CCC(=O)O)c2c1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
The crude malonic acid 13 (250 mg, 0.957 mmol) was placed in a round bottom flask under vacuum and slowly heated to between 150 and 200° C., as the evolution of CO2 occurred. As the bubbling ended, the reaction was heated for 2 more additional minutes, then allowed to cool to room temperature. The product was purified by flash chromatography three times using 0 to 10% MeOH in CHCl3 to give compound 14 as a solid (120 mg; 57.7% yield; M−1=216.3).
Reaction SMILES: O[C:2]1([C:16]([OH:18])=[O:17])[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][C:3]1([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][C:6](=[O:8])[CH:7]=[C:2]1[C:16]([OH:18])=[O:17]
Reactant: CC1(c2ccccc2)CCC(=O)CC1(O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccccc2)CCC(=O)C=C1C(=O)O
Temperature: 0 °C
Yield: 69.1 %

Procedure:
4.4 g (17.6 mmol) of (1RS,2RS)-1-hydroxy-2-methyl-5-oxo-2-phenylcyclohexane-1-carboxylic acid were heated at reflux for one hour in 100 cm3 of toluene in the presence of 0.34 g of para-toluenesulphonic acid. The reaction mixture was cooled to 0° C. and the precipitate formed was filtered off, washed with ethyl ether and then dried at 50° C. 2.8 g (69%) of (RS)-2-methyl-5-oxo-2-phenylcyclohexene-1-carboxylic acid were thus obtained in the form of a pink solid, the characteristics of which were as follows:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][N:23]([C:26]([N:28]6[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]6)=[O:27])[CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[CH2:35][CH:36]1[CH2:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][N:23]([C:26]([N:28]6[CH2:29][CH2:30][N:31]([CH2:35][CH:36]7[CH2:39][CH2:38][CH2:37]7)[CH2:32][CH2:33]6)=[O:27])[CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: BrCC1CCC1
Reactant: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)N1CCN(CC2CCC2)CC1

Procedure:
The reaction mixture derived from the preparation of {4-[4-(benzothiazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridin-1-yl}-piperazin-1-ylmethanone (EXAMPLE 154) was reacted with (bromomethyl)cyclobutane (90 mg, 5 eq.) in the presence of DIPEA at 60° C. for 72 h before the mixture was purified by HPLC, giving the title compound as yellow powder. 1H NMR (400 MHz, DMSO-d6): δ=11.78 (s, 1H), 9.52 (s, 1H), 9.16 (s, 1H), 8.84 (d, 1H, J=2.0 Hz), 8.26 (s, 1H), 8.14 (s, 1H), 7.97 (d, 1H, J=8.9 Hz), 7.91 (s, 1H), 7.80 (dd, 1H, J=2.0 Hz & 8.9 Hz), 6.82 (d, 1H, J=1.7 Hz), 6.57 (br s, 1H), 3.94 (s, 2H), 3.46 (m, 4H), 3.36 (m, 4H), 3.18 (m, 4H), 2.54 (br s, 2H), 2.46 (m, 1H), 2.34 (m, 3H), 2.03 (m, 1H), 1.84 (m, 1H), 1.65 (m, 1H). LC/MS: m/z 529.17 (15) [MH+], tR=1.94 (ZQ2000, polar—5 min).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([CH3:46])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[C:25]([C:37]([NH:39][C:40]3[S:44][N:43]=[C:42]([CH3:45])[N:41]=3)=[O:38])=[N:26][C:27]([S:30][C:31]3[N:35]([CH3:36])[CH:34]=[N:33][N:32]=3)=[CH:28][CH:29]=2)=[CH:19][CH:18]=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:12][N+:13]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[C:25]([C:37]([NH:39][C:40]3[S:44][N:43]=[C:42]([CH3:45])[N:41]=3)=[O:38])=[N:26][C:27]([S:30][C:31]3[N:35]([CH3:36])[CH:34]=[N:33][N:32]=3)=[CH:28][CH:29]=2)=[CH:19][CH:18]=1)([CH3:46])[O-:9]
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCCN(C)C)cc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCC[N+](C)(C)[O-])cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
At 0° C., 9.2 mg of m-chloroperbenzoic acid was added to a chloroform solution of 20 mg of 3-({4-[2-(dimethylamino)ethoxy]phenyl}thio)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Example 1, and stirred at 0° C. for 30 minutes. Aqueous sodium sulfite solution was added to it, extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid]. The solvent of the obtained fraction was evaporated away under reduced pressure to obtain 17.5 mg of the entitled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](O)=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:21]>O>[Cl:21][C:17]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: COc1ccc(-n2nc3ccccc3c2O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-n2nc3ccccc3c2Cl)cc1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
To a mixture of the product from step 2 (12.0 g, 0.05 mol) in acetanotrile (250 mL) was added POCl3 (11.5 g, 0.74 mol), and heated to 80° C. for 4 h. After the reaction mixture was cooled to room temperature, water (500 ml) was added. The product was collected on a filter, and washed with water. After dried under vacuum, the title compound (8 g, 67%) was obtained; MS (ESI+) m/z 259 (M+1, 100).