Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:32][CH:33]=O)=[CH:27][CH:26]=1>>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:17][CH2:18][N:19]([CH2:33][CH2:32][CH:31]([C:28]5[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=5)[C:35]5[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=5)[CH2:20][CH2:21]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Reactant: COc1ccc(C(CC=O)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(CCN2CCN(c3ccc4c(c3)C(=O)N(C3CCCCC3)C4)CC2)c2ccc(OC)cc2)cc1
Yield: 59.8 %

Procedure:
In the same manner as in Example 38, the title compound (52 mg) was prepared from the compound (47 mg) obtained in step (e) of Example 1 and the compound (110 mg) obtained in step (b).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.N#N.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(NC(C)C)(C)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu](I)I>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: N#N
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc(C#Cc2ccccc2)cs1
Temperature: 70 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
Under a N2 atmosphere, 4-bromothiophene-2-carbaldehyde (1.0 g, 5.2 mmol) was taken up in diisopropylamine (20 mL). TPP (549 mg, 2.1 mmol), bis(benzonitrile)palladium chloride ([Pd(PhCN)2]Cl2) (400 mg, 1.0 mmol), and copper iodide (199 mg, 1.0 mmol) were added. The mixture was degassed with N2 before phenylacetylene (1.15 mL, 10.4 mmol) was added, and the reaction was stirred at 70° C. for 16 h. The mixture was concentrated to a dark brown solid and chromatographed in 0-15% EtOAc in heptane to yield 4-(phenylethynyl)thiophene-2-carbaldehyde (981 mg, 88%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.93 (d, 1H), 7.88 (t, 1H), 7.85 (d, 1H), 7.53 (m, 2H), 7.38 (m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C[N:16]1C[CH2:19][CH2:18][C:17]1=O.C(N)CC>O>[CH2:17]([NH:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:18][CH3:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CN1CCCC1=O
Solvent: O
Solvent: CCCN
Product: CCCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5.23 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.69 g of n-propylamine under ice cool, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water, and the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 2.78 g of N-propyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([NH:14][C:15]([C:17]2[C:18]([NH:25][CH2:26][CH:27]3[CH2:34][CH2:33][C:30]4([CH2:32][CH2:31]4)[CH2:29][CH2:28]3)=[N:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].[CH:55](I)([CH3:57])[CH3:56]>C(Cl)Cl.CCOC(C)=O>[CH2:35]([C:11]1([NH:14][C:15]([C:17]2[C:18]([NH:25][CH2:26][CH:27]3[CH2:34][CH2:33][C:30]4([CH2:31][CH2:32]4)[CH2:29][CH2:28]3)=[N:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=2)=[O:16])[CH2:12][CH2:13][N:8]([CH:55]([CH3:57])[CH3:56])[CH2:9][CH2:10]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(NC(=O)c2cnc(C#N)nc2NCC2CCC3(CC2)CC3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(Cc2ccccc2)(NC(=O)c2cnc(C#N)nc2NCC2CCC3(CC2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyl-4-({2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]-pyrimidine-5-carbonyl}amino)piperidine-1-carboxylic acid tert-butyl ester (0.14 mmol) in CH2Cl2 (1.5 mL) is added TFA (0.4 mL) at 0° C. After stirring at room temperature for 0.5 h, the reaction mixture is concentrated in vacuo. The residue is dissolved in DMF (1.5 mL) and treated with K2CO3 (0.35 mmol) and isopropyl iodide (0.28 mmol) at 0° C. After stirring at room temperature for 5 h, the reaction mixture is diluted with AcOEt and washed with H2O and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by RP-HPLC to give the title compound; 1H NMR (CDCl3), δ: 0.18-0.26 (2H, m), 0.27-0.34 (2H, m), 0.91-0.99 (2H, m), 1.01-1.13 (6H, s), 1.17-1.33 (2H, m), 1.63-1.97 (7H, m), 2.15-2.40 (4H, m), 2.64-2.90 (3H, m), 3.15 (2H, s), 3.46 (2H, dd), 5.28 (1H, s), 7.02-7.10 (2H, m), 7.20-7.30 (3H, m), 8.05 (1H, s), 8.70 (1H, bs).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[ClH:24].[N:11]1([CH2:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
4-(2-Oxo-2-p-tolyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E36.1 (661 mg, 2.08 mmol) was dissolved in 4M HCl solution in dioxan (25 ml) at 0° C. and the mixture was stirred for 45 min at room temperature. Solvents were concentrated in vacuo and azeotroped with diethyl ether to yield the title compound (536 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:19]([CH2:18][O:17][CH3:16])=[N:15][N:14]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(-c2cccc(Cl)c2)nn1
Reactant: COCC(=O)Cl
Product: COCc1nnc2ccc(-c3cccc(Cl)c3)nn12

Procedure:
As for Example 4, 6-(3-chlorophenyl)-3-hydrazinopyridazine (prepared as in Example 51 of U.S. Pat. No. 4,112,095) is reacted with methoxyacetyl chloride to give the product of the Example.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:7]([C:22]([O:24][CH3:25])=[O:23])=[C:6]2[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34]C)=[C:28]([O:36][CH3:37])[CH:27]=1.Cl.O1CCOCC1.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:7]([C:22]([O:24][CH3:25])=[O:23])=[C:6]2[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([OH:34])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1N1CCOCC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2cc(OC)c(O)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1N1CCOCC1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A mixture of the compound obtained in Example 118 (1.3 g), conc.hydrochloric acid (15 ml) and dioxane (15 ml) is heated under reflux overnight. The reaction mixture is cooled to room temperature, and thereto are added water and chloroform. The extract is washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=50:1) to give 6,7-dimethoxy-4-(3,5-dimethoxy-4-hydroxyphenyl)-3-methoxycarbonyl-2-morpholino-1(2H)-isoquinolinone (530 mg) as listed in Table 10.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:10]=[C:9]1[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.CN(C)C=O>ClCCl.C(=O)(O)[O-].[Na+]>[N:32]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOS(C)(=O)=O)CC1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Temperature: 50 °C
Yield: 93 %

Procedure:
Combine tert-butyl 4-(1-(2-(methylsulfonyloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.02 g, 4.42 mmol), pyrrolidine (1.1 mL, 3.0 eq), and dimethylformamide (19 mL). Heat the reaction mixture to 50° C. overnight. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate the layers. Wash the organics with water. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to ethyl acetate to 10% methanol in dichloromethane, to give the title compound as a yellow oil (1.79 g, 93%). MS (ES) m/z=433 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[O:20][S:19](=[O:38])[O:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:40].[Na+]>O.[Ru](Cl)(Cl)Cl.ClCCl.C(#N)C>[CH2:31]([O:30][C:24]1[CH:23]=[C:22]([C@H:21]2[C@H:17]([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[O:18][S:19](=[O:40])(=[O:38])[O:20]2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc([C@@H]2OS(=O)O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COc1ccc([C@@H]2OS(=O)(=O)O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
Mixture: 33 g (63 mmol) of (4S,5S)-4,5-bis(3'-benzyloxy-4'-methoxyphenyl)-2-oxo-1,3,2-dioxathiolane, 300 ml of dichloromethane/acetonitrile 1:1, 200 ml of ice-water, 72.7 mg (0.35 mmol) of ruthenium (III) chloride hydrate, 26.83 g (125.4 mmol) of sodium metaperiodate.
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:41]I>C(Cl)Cl>[I:41][CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CO)CN1C(=O)CCc2ccccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CI)CN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
A reaction flask was charged with (S)-1-(3-Hydroxy-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH16) (1.54 g, 7.0 mmol) dissolved in 50 mL DCM. PPh3 (4.04 g, 15.4 mmol) and imidazole (1.14 g, 16.7 mmol) were added followed by stirring at rt for 15 min. The mixture was cooled with an ice-bath followed by addition of I2 (5.00 g, 19.7 mmol). The reaction mixture was slowly warmed to rt and stirred over night. The reaction mixture was washed with a Na2S2O3 solution, dried over Na2SO4, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 1:1) to give the title compound (122LH18) (2.140 g, 93%).
Reaction SMILES: [CH3:1][NH:2]N.[C:4]([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=[CH:15]/[C@H:16]2[O:21][CH2:20][C@H:19]([S:22][C@H:23]([CH3:55])[C@@:24]([O:39][C:40](=[O:54])[CH2:41][CH2:42][N:43]3C(=O)C4C(=CC=CC=4)C3=O)([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])[CH2:25][N:26]3[CH:30]=NC=[N:27]3)[CH2:18][O:17]2)=[C:8]([F:56])[CH:7]=1)#[N:5]>ClCCl>[C:4]([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=[CH:15]/[C@H:16]2[O:21][CH2:20][C@H:19]([S:22][C@H:23]([CH3:55])[C@@:24]([O:39][C:40](=[O:54])[CH2:41][CH2:42][NH2:43])([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])[CH2:25][N:26]3[CH:30]=[CH:1][N:2]=[N:27]3)[CH2:18][O:17]2)=[C:8]([F:56])[CH:7]=1)#[N:5]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)CCN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1F
Reactant: CNN
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1ccnn1)(OC(=O)CCN)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
222.7 mg (4.38 mmol) of methylhydrazine were added to a solution of 100 mg (0.13 mmol) of [(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl]3-(1,3-dioxo-1,3-dihydro-2-isoindolyl)propionate [prepared as described in Step 13(i) above] in 2 ml of dichloromethane in an ice bath. The resulting mixture was stirred at ambient temperature for 20 hours. At the end of this time, the reaction mixture was concentrated and then evaporated to dryness in vacuo. Dichloromethane was added to the resulting residue and the dichloromethane was then evaporated under reduced pressure. The resulting residue was then dissolved in dichloromethane, the solution was allowed to stand at ambient temperature for 12 hours and then concentrated. The residue thus obtained was purified by chromatography on a silica gel (15 g) column using a 9:1 mixture of ethyl acetate and methanol to give 41.5 mg (yield 50%) of the title compound as a pale yellow non-crystalline solid.
Reaction SMILES: C(=O)(OC)O[CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>CCO.CCOCC>[CH3:15][O:16][CH2:17][CH2:18][NH:19][C@H:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH2:3]
Reactant: COCCN
Reactant: COC(=O)OC/C=C/c1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: C=C[C@H](NCCOC)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
To a solution of (E)-cinnamyl methyl carbonate (0.50 g) in EtOH (10 mL) at RT under N2 was added the (S)-(1,1′-Dinaphthyl-2,2′-di-(S,S)-1-phenylethylphosphoramidite (0.140 g), [Ir(COD)Cl]2 (0.035 g) and 2-methoxyethylamine (0.39 g). The reaction mixture was stirred at 50° C. for 1.5 h, then cooled to RT. The reaction mixture was diluted with ether and washed with 2N HCl (×3). The combined acidic aqueous layer was made basic with aqueous 2N NaOH and extracted with DCM (×3). The combined DCM layer was washed with brine, dried (Na2SO4), filtered and evaporated The crude material was purified via column chromatography (gradient—5%, 10%, 15% EtOAc/hexanes) to give the desired product (0.375 g, 74% ee, 75% yield). 1H NMR (300 MHz, CDCl3) δ 2.62-2.81 (m, 2H), 3.34 (s, 3H), 3.49 (t, 2H), 4.18 (d, 1H), 5.09 (d, 1H), 5.20 (dd, 1H), 5.88-5.99 (m, 1H), 7.22-7.35 (m, 5H). MS APCI, m/z=192 (M+1). LC/MS 0.66 min., Method A.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH2:3]1.[C:14]([O:18][C:19]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=S)=[O:20])([CH3:17])([CH3:16])[CH3:15].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:14]([O:18][C:19]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[N:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH2:3]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccnc(N2CCC(N)C2)c1
Reactant: CCNC(=S)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=NC1CCN(c2cc(C)ccn2)C1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a solution of 3-amino-1-(4-methylpyridin-2-yl)pyrrolidine (177 mg) and N-(tert-butoxycarbonyl)-N′-ethylthiourea (245 mg) in N,N-dimethylformamide (5 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (230 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate, washed with water three times and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, 5% methanol in dichloromethane) to give N-(tert-butoxycarbonyl)-N′-ethyl-N″-(1-(4-methylpyridin-2-yl)-pyrrolidin-3-yl)guanidine (290 mg).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:14]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=3)(=[O:32])=[O:31])[N:13]=2)[CH:7]=1.[OH-].[Na+].C(Cl)Cl.CCOC(C)=O>CO>[CH3:19][O:18][C:16]1[C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[C:14]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=2)(=[O:32])=[O:31])[N:13]=[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C:3]([OH:40])=[O:2])[N:17]=1
Reactant: COC(=O)COc1cccc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(OCC(=O)O)c2)nc1OC
Reaction time: 1 h

Procedure:
85 mg of {3-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-phenoxy}-acetic acid methyl ester, product of example 2, dissolved in MeOH (30 ml) were treated at RT with 1N NaOH (0.9 ml) and the solution was stirred for 1 h until the transformation was complete according to TLC analysis (CH2Cl2/EtOAc: 3:1). The reaction mixture was partitioned between 1N HCl and CH2Cl2, the organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue upon triturating with ether provided the desired {3-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-phenoxy}-acetic acid as a white solid. ISN mass spectrum, m/e 551 (M−1 calculated for C26H24N4O8S: 551).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7](/[CH:20]=[CH:21]/[S:22]([NH2:25])(=[O:24])=[O:23])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[CH3:3].S(NN)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:20][CH2:21][S:22]([NH2:25])(=[O:23])=[O:24])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[CH3:3]
Reactant: CSc1ccc(Oc2ccc(/C=C/S(N)(=O)=O)cc2CN(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: Cc1ccccc1
Product: CSc1ccc(Oc2ccc(CCS(N)(=O)=O)cc2CN(C)C)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
The vinylsulfonamide from example 67 (1.26 g, 3.33 mmol) was heated together with tosyl hydrazine (6.20 g, 33.3 mmol) in toluene at reflux for 5 h. After cooling to rt the solvent was evaporated and the residue partitioned between EtOAc (50 mL) and sat. NaHCO3 (50 mL). The organic layer was separated, washed with water (20 mL), brine (20 mL) and then dried (MgSO4) and evaporated. The residue was purified by flash chromatography [SiO2; (EtOAc/ MeOH/ 880 NH3; 100:5:0.5)/ pentane; 3:1→1:0] to afford the desired product as a cream powder (1.055 g, 83%); Free base: δH(CD3OD, 400 MHz) 2.27 (6 H, s), 2.47 (3 H, s), 3.09-3.13 (2 H, m), 3.30-3.36 (2 H, m), 3.50 (2 H, m), 6.83 (1 H, d), 6.87 (2 H, d), 7.19 (1 H, d), 7.27 (2 H, d), 7.35 (1 H, s); MS m/z (TS+) 381 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH2:29][N:1]3[CH:2]([C:11]4[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=4[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])[CH:31]=[CH:32][N:33]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=Cc1ccnc(-n2cccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 392.88 g/mol.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:27][C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:19])=[CH:14][CH:13]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CCO
Product: COc1ccc(-c2c(N[C@H](C)c3ccccc3)c(=O)c2=O)cc1
Yield: 64.1 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (150 g, 0.609 mmol) and (R)-(+)-α-methyl-benzylamine (180 μL, 0.914 mmol) in ethanol (1 mL) were converted to the title compound (120 mg, 64%) m.p.: 158.7-160.1° C.; 1H NMR (DMSO-d6) δ9.28(d,1H), 8.04(ABq,2H), 7.35(m,5H), 7.10(ABq,2H), 3.83(s,3H), 1.64(d,3H); IR (KBr) 3260, 3060, 3030, 2970, 1770, 1720, 1600, 1560, 1520, 1440, 1410, 1380, 1340, 1310, 1260, 1220, 1180, 1120, 1100, 1025, 825, 700 cm−1; MS (m/z) 307 [M+],
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])[CH2:3]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)azetidine (3.52 g, 14.0 mmol) (obtained as described in Reference Example 54(1)) in methylene chloride (106 ml) were added methanesulfonyl chloride (1.19 ml, 15.4 mmol) and triethylamine (2.16 ml, 15.4 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1→1:3) as the eluant to afford 3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)-azetidine (4.63 g, yield 100%) as pale yellow crystals.