Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[C:16]([O:18]CC)=[O:17])=[CH:9][CH:8]=1)[CH:4]=[CH2:5]>CO.C1COCC1>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
NaOH (6 N aqueous solution, 10 mL) was added to a solution of (trans)-ethyl 2-(4-(allyloxy)phenyl)cyclopropanecarboxylate (Intermediate F, 11.15 g, 45.27 mmol) in methanol (30 mL) and THF (25 mL) and stirred at room temperature for 18 h. After removal of the solvent, the residue was dissolved in CH2Cl2 (200 mL), acidified with HCl (10% aqueous solution, 30 mL), and washed with brine (2×200 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. Removal of the solvent afforded 9.13 of (trans)-2-[4-(allyloxy)phenyl]cyclopropanecarboxylic acid [Rf=0.25 (5% MeOH/CH2Cl2), white solid, 92% yield]
Reaction SMILES: N=C=N.[C:4]1([CH3:21])[CH:9]=[CH:8][C:7]([S:10]([NH:13][C@H:14]([C:18](O)=[O:19])[CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.[NH2:23][CH:24]([CH:32]([OH:59])[CH:33]([NH:41][C:42](=[O:58])[C@H:43]([CH:55]([CH3:57])[CH3:56])[NH:44][S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:51]1([CH3:54])[CH:52]=[CH:53][C:48]([S:45]([NH:44][C@H:43]([C:42]([NH:41][CH:33]([CH:32]([OH:59])[CH:24]([NH:23][C:18](=[O:19])[C@H:14]([CH:15]([CH3:17])[CH3:16])[NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:21])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:58])[CH:55]([CH3:57])[CH3:56])(=[O:46])=[O:47])=[CH:49][CH:50]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](C(=O)NC(Cc2ccccc2)C(O)C(N)Cc2ccccc2)C(C)C)cc1
Agent: Cl
Agent: N=C=N
Product: Cc1ccc(S(=O)(=O)N[C@H](C(=O)NC(Cc2ccccc2)C(O)C(Cc2ccccc2)NC(=O)[C@@H](NS(=O)(=O)c2ccc(C)cc2)C(C)C)C(C)C)cc1

Procedure:
According to the carbodiimide coupling procedure of Example 55, N-(p-toluenesulfonyl)valine was coupled to the resultant compound of Example 112 to give the desired compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O1CCC[CH2:16]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.CCCCCC.C(OCC)(=O)C>[CH2:16]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 986 mg of methyltriphenylphosphonium bromide in 20 ml of tetrahydrofuran, 1.87 ml of 1.63 M n-butyl lithium/hexane solution was added dropwise at 0° C., under cooling with ice. The temperature then was immediately raised to room temperature, and the system was stirred for 50 minutes. The reaction liquid was again cooled to 0° C., to which a solution of 500 mg of t-butyl 4-oxotetrahydropyridine-1(2H)-carboxylate in 5 ml of tetrahydrofuran was added dropwise, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to provide 192 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=[C:42]([OH:55])[CH:41]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:44]2[CH:45]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:41]=[C:42]([OH:55])[CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cc(O)cc(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(NS(=O)(=O)c4ccc(F)cc4)c3)n(-c3ccccc3)c(=O)c12
Yield: 60.9 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.11 mmol) was treated with 4-fluoro-N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (69 mg, 0.18 mmol), cesium carbonate (2M, 180 μl, 0.36 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol) according to the method described in Example 3 to give 42 mg (56% yield) of the title compound. Purity 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:22])[C:19]([Cl:21])=[O:20]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:18](=[O:22])[C:19]([Cl:21])=[O:20])=[CH:8]2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Clc1ccc(Cn2ccc3ccccc32)cc1
Solvent: CCOCC
Product: O=C(Cl)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(4-chlorobenzyl)-1H-indole (2.0 g) in dry ethyl ether (5 ml) kept under stirring and cooled to 0° C. is added drop by drop with a solution of oxalyl chloride (0.85 ml) in dry ethyl ether (2 ml). Afterwards the reaction is left at room temperature for 2 h. The separated solid is recovered by filtration, washed with dry ethyl ether and dried under vacuum at 40° C. to give 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride (1.64 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:22]([CH:25]=[C:26]=[O:27])(=[O:24])[CH3:23]>C1(C)C=CC=CC=1>[CH2:10]([N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:26](=[O:27])[CH2:25][C:22](=[O:24])[CH3:23])=[CH:7][C:2]=1[F:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)C=C=O
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1F
Solvent: Cc1ccccc1
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 2-fluoro-N1,N1-dihexylbenzene-1,4-diamine (2.94 g, 10.0 mmol) in toluene (50 mL) was added acetyl ketene (0.84 g, 10.0 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:4) to give the title compound as yellow oil (2.67 g, 70%).
Reaction SMILES: [OH:1][CH:2]([CH3:17])[CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].[CH2:18]([NH2:21])[CH2:19][NH2:20]>C(O)(C)C.O>[OH:1][CH:2]([CH3:17])[CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:20][CH2:19][CH2:18][NH2:21])(=[O:6])=[O:5]
Reactant: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCN
Solvent: CC(C)O
Solvent: O
Product: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCCN

Procedure:
28 g (0.1 mol) of 2-chloro-5-nitrophenyl 2-hydroxypropyl sulphone are refluxed in 100 ml of isopropanol. To this are added gradually 15 ml of ethylenediamine, and heating is continued with stirring for a further hour. The cold reaction solution is diluted with 300 ml of water and stirred at 20° C. for two hours. The precipitated yellowish crystals are filtered off with suction, washed with 100 ml of water and dried. This gives 28 g of uniform 2-(2-aminoethylamino)-5-nitrophenyl 2-hydroxypropyl sulphone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:11]1([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:24][C:21]3[CH:22]=[CH:23][C:18]([NH2:17])=[CH:19][CH:20]=3)[CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)cc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a 10 mL sealed tube with stirbar was added 7-chloro-2-phenylfuro[3,2-b]pyridine (300.00 mg; 1.31 mmol; 1.00 eq.), 4-aminophenol (285.09 mg; 2.61 mmol; 2.00 eq.), and caesium carbonate (1 702.45 mg; 5.22 mmol; 4.00 eq.). The mixture was suspended in DMF (7.00 ml) and stirred at 125° C. overnight. The reaction mixture was cooled to room temperature and poured into 150 mL water. Filtered to collect precipitate, washing with water and hexane. The resulting crude material was purified by Biotage chromatography using a KP-NH column (10-50% EtOAc/Hex) to afford the title compound as a beige solid (216 mg, 55%). (HPLC (method F): 99%, RT: 4.73 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.29 (d, J=5.5, 1H), 7.96 (d, J=7.2, 2H), 7.66 (s, 1H), 7.54 (t, J=7.4, 3H), 7.47 (t, J=7.3, 1H), 6.99 (d, J=8.7, 2H), 6.67 (d, J=8.7, 2H), 6.56 (d, J=5.5, 1H), 5.20 (s, 2H); MS (m/z) 303 [M+H]+, RT: 2.6 min.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Product: O=CC=Cc1ccc(-c2cncnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-pyrimidinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=1)=[O:3].[NH3:20]>O1CCCC1>[O:17]=[C:8]1[C:7]2[CH:18]=[CH:19][C:4]([C:2]([NH2:20])=[O:3])=[CH:5][C:6]=2[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[NH:9]1
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O

Procedure:
Dissolve the acid chloride from Step A in 20 ml. of dry tetrahydrofuran and add this solution dropwise with stirring to a cooled (ice-bath) saturated solution of ammonia in 60 ml of tetrahydrofuran. Pass ammonia through the reaction mixture simultaneously for 15 minutes. Stir at room temperature for an additional 15 minutes and evaporate the reaction mixture to dryness. Add a mixture of 12 ml of ethanol and 60 ml of water to the residue and stir at room temperature for an additional 30 minutes. Separate the solid by filtration and wash with water, then with ethanol and then with ether. Dry in vacuo to obtain the title product.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.Br[C:25]1[CH:26]=[C:27]([C:30]#[N:31])[S:28][CH:29]=1>>[C:30]([C:27]1[S:28][CH:29]=[C:25]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:26]=1)#[N:31]
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Product: CC1=CC(C)(C)Nc2ccc(-c3csc(C#N)c3)cc21
Yield: 90.6 %

Procedure:
This compound was prepared by General Method 2 from compound 9 (200 mg, 0.63 mmol) and 4-bromo-2-cyanothiophene (0.50 g, 2.65 mmol). The crude product was purified by prep. TLC (20×20 cm, 1000 μm, 25% ETOAc:Hexane) to afford 160 mg (91%) of Compound 452 as a yellow oil. Data for Compound 452:Rf 0.50 (silica gel, 25% EtOAc:hex); 1H NMR(400 MHz, CDCl3) 7.79 (s, 1H), 7.46 (s, 1H), 7.20 (s, 1H), 7.16 (d, J=8.3, 1H), 6.46 (d, J=8.3, 1H), 5.37 (s, 1H), 2.03 (s, 3H), 1.31 (s, 6H); IR (film, NaCl) 1159, 1381, 1402, 1449, 1476, 1499, 1609, 1653, 2216, 2915, 3294, 3584.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].[Cl-].[Na+]>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][NH:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:11]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of (2-aminoethyl)carbamic acid tert-butyl ester (from Step 6 below) (4.2 g, 26.3 mmol) in methylene chloride (50 mL) was added triethylamine (4.4 mL, 31.4 mmol) and methyl bromoacetate (2.4 mL, 26.3 mmol). The reaction was stirred overnight at room temperature. A saturated aqueous solution of sodium chloride (100 mL) was then added, and the organic layer was separated dried over MgSO4, filtered and concentrated. The residue was taken up in diethyl ether, and a saturated solution of HCl in diethyl ether was added to precipitate the product, which was filtered, and dried. It was recrystallized in ethanol/ethyl acetate, to give a white solid; 1.39 g (20% yield). MS-APCI: M+1=233.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH2:12]([CH:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:15](OC)=[O:16])[CH3:13]>C1(C)C(C)=CC=CC=1>[CH3:22][CH2:21][CH2:20][CH2:19][CH:14]([C:15]([CH2:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[O:16])[CH2:12][CH3:13]
Reactant: CC(=O)c1ccccc1
Reactant: CCCCC(CC)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCC(CC)C(=O)CC(=O)c1ccccc1
Yield: 81 %

Procedure:
The conditions of Example 1 were repeated except that the following amounts were used: 60% sodium hydride in mineral oil (200 g, 5.03 mol. 2.0 mol/mol acetophenone), methyl 2-ethylhexanoate (618 g, 3.91 mol, 1.5 mol/mol acetophenone), xylene (449 g), and then a solution of acetophenone (304 g, 2.53 mol) in xylene (180 g) was added over 1 h. The mixture was kept at reflux for an additional 30 min. Workup of the reaction mixture gave material having product in a crude yield of 89%. Vacuum distillation (200 mtorr) through a 15 cm Vigreux column yielded the product in the heart cut: 4-ethyl-1-phenyl-1,3-octadione (523 g, 97% pure, 2.06 mol; 81% yield; bp: 128-169° C.). Dypnone was undetectable in the product.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[N:19]=[C:18]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])[C:17]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:16][C:15]=2[F:35])(=[O:13])=[O:12])=[CH:7][CH:6]=1>ClCCl>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([C:14]2[N:19]=[C:18]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])[C:17]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:16][C:15]=2[F:35])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)C=Cc1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCc1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A Raney nickel suspension (“R-100”, product of Nikko Rica Corporation) (1 ml) was washed sequentially with water and ethanol to give an ethanol (10 ml) suspension. The resulting suspension was added to an ethanol (40 ml) solution of methyl 3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]acrylate (1.38 g, 2.86 mmol). Under a hydrogen atmosphere, the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane. The resulting solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 1.37 g, 2.83 mmol, 99%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:12].ClC(Cl)(Cl)[C:28]([N-:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29].C(=O)([O-])[O-].[K+].[K+].Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:28]([NH:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:29])(=[O:23])=[O:24])=[CH:20][CH:21]=1)=[O:12]
Reactant: O=C([N-]C1CCCCC1)C(Cl)(Cl)Cl
Reactant: NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Temperature: 160 °C

Procedure:
3.6 g of 4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfon-amide are carefully mixed with 2.5 g of trichloroacetyl-cyclohexyl amide and 2.8 g of potassium carbonate and the mixture is heated in a bath for 1 hour at 160° C. After cooling, the reaction mixture is treated with water and hydrochloric acid, filtered off with suction and the reaction product is reprecipitated from very dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-urea obtained melts at 214°-216° C.
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:17][NH2:18]>CCO>[NH2:6][C:5]1[NH:18][N:17]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: NN
Reactant: CSC(Nc1ccccc1)=C(C#N)C#N
Solvent: O
Solvent: CCO
Product: N#Cc1c(Nc2ccccc2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((methylthio)(phenylamino)methylene)malononitrile (3.2 g) in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(phenylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: N[C:2]1[C:3]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.N([O-])=O.[Na+].[ClH:18]>[Cu]>[Cl:18][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CCCCN)c(N)c1
Reactant: Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cnc(CCCCN)c(Cl)c1

Procedure:
Reaction of 3-amino-2-(4-aminobutyl)-5-methylpyridine from Example 1(d) (0.5 g) with sodium nitrite, cuprous chloride, copper bronze and hydrochloric acid under conditions analogous to those of Example 1(e) gave 3-chloro-2-(4-aminobutyl)-5-methylpyridine (0.43 g) as an oil. N.M.R. (CDCl3) assignment δ(p.p.m.), multiplicity; NH2, 1.56, s; CH2 (CH2)2CH2NH2, 1.4-1.9, m; 5--CH3, 2.29, s; --CH2NH2, 2.74; m; --CH2 (CH2)3NH2, 2.91, m; 4H+6H pyridyl protons, 7.45+8.24, m×2;
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=3[CH:17]=2)=O)[CH:11]=[CH:12][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[I:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:25]=2[CH3:26])[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]3([CH3:30])[CH3:29])=[CH2:1])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc2c(cc1C(=O)c1cccc(I)c1)C(C)(C)CCC2(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1cccc(I)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium tert-butoxide (7.26 g, 64.8 [lacuna]) is added to a solution of 3-iodophenyl-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-methanone (20 g, 46.3 mmol) and methyltriphenylphosphonium bromide (21.5 g, 60.2 mmol) in THF (100 ml). The mixture is stirred for 20 h at room temperature. The solution is extracted with ethyl acetate. After separation of the phases by settling, the organic phase is washed twice with 40 ml of water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20]CC=C)=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:24])=[C:10]1[CH3:25])=[O:4].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:24])=[C:10]1[CH3:25])=[O:4]
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of allyl 1-(3-(methoxycarbonyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (133 mg, 0.35 mmol) and morpholine (0.3 mL, 3.4 mmol) in THF (4 mL) was degassed and then Pd(PPh3)4 (41 mg, 0.035 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was dissolved in Methanol and acidified to pH 4. The precipitate was collected and washed with water to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[Na].C(O)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=1)[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.9 g (10 mmol) 1,3-dihydro-5(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4 thiadiazin-5-yl)-3,3 dimethyl-2H-indol-2-one (Example 3), 0.4 g (10 mmol) sodium hydroxyde and 100 ml ethanol were refluxed 30mn. After evaporation of the solvent, the residue was dissolved in 50 ml DMF and 1.86 g (10 mmol) p-nitrobenzoyl chloride were added while keeping the temperature under 30° C. The mixture was stirred 2 hrs at room temperature, diluted with 100 ml water, extracted with ethyl acetate. The organic layers were washed with brine and dried over magnesium sulfate. The residue was purified by column chfomatography on silica (eluent:ethylacetate/hexane:1/1) and the major fraction was triturated in isopropyl ether and dried under vacuum.