Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11](CC2C=CC([N+]([O-])=O)=CC=2)[CH2:10][CH2:9]1>[Cl-].[Cl-].[Cl-].[Ti+3]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([C:6]2[CH:5]=[CH:4][C:3]([NH2:8])=[CH:2][CH:7]=2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3ccccc3Cl)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(N2CCN(c3ccccc3Cl)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(o-chlorophenyl)-4(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(o-chlorophenyl)-4-[(4-aminophenyl)]piperazine.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]3[N:10]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH:11]=[C:12](I)[C:7]3=[CH:6][C:5]=2[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH2:3][CH2:2]1.[F:43][C:44]1[CH:45]=[C:46]([CH:64]=[CH:65][CH:66]=1)[CH2:47][N:48]1[C:52]([CH3:53])=[C:51](B2OC(C)(C)C(C)(C)O2)[C:50]([CH3:63])=[N:49]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[CH:1]1([C:4]2[N:9]=[C:8]3[N:10]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH:11]=[C:12]([C:51]4[C:50]([CH3:63])=[N:49][N:48]([CH2:47][C:46]5[CH:64]=[CH:65][CH:66]=[C:44]([F:43])[CH:45]=5)[C:52]=4[CH3:53])[C:7]3=[CH:6][C:5]=2[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)c(C4CC4)nc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)c(C4CC4)nc32)cc1
Yield: 90.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(6-cyclopropyl-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 47) (115 mg, 0.161 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (81.53 mg, 0.24 mmol) in sodium carbonate (51.9 mg, 0.483 mmol), Pd(PPh3)2Cl2 (5.6 mg, 0.008 mmol), 1,2-dimethoxyethane/water (10/2 ml) to afford 113 mg (89% yield) of titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:7]([CH2:13][NH2:14])[CH2:6]2.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18]>CC1OCCC1>[CH2:17]([O:16][C:15](=[O:19])[NH:14][CH2:13][C@H:7]1[CH2:6][C:5]2[C:8]1=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:18]
Reactant: COc1cc2c(cc1OC)C(CN)C2
Reactant: CCOC(=O)OCC
Solvent: CC1CCCO1
Product: CCOC(=O)NC[C@H]1Cc2cc(OC)c(OC)cc21

Procedure:
5 mg of 1-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methanamine and 12.6 mg (10 eq) of diethyl carbonate are dissolved in 2-MeTHF.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(-c2csc(N)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2csc(NS(=O)(=O)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(2-amino-thiazol-4-yl)-benzoic acid methyl ester (1.17 g, 5 mmol), benzenesulfonyl chloride (1.06 g, 6 mmol) and 4-dimethylaminopyridine (2.20 g, 18 mmol) in CH2Cl2 (50 mL) was stirred at room temp for 18 h. A white solid was provided as 4-(2-benzenesulfonylamino-thiazol-4-yl)-benzoic acid methyl ester.
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:5].[C:31]12(C(Cl)=O)[CH2:40]C3CC(CC(C3)[CH2:32]1)[CH2:38]2>>[C:3]12([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[O:5])[CH2:40][CH:31]3[CH2:38][CH:28]([CH2:29][CH:30]([CH2:32]3)[CH2:2]1)[CH2:27]2
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccccc1F
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)C12CC3CC(CC(C3)C1)C2
Yield: 6 %

Procedure:
According to the method used for the synthesis of the compound 28a, the titled compound (110 mg) is synthesized by using tert-butyl((2-trimethylstannylphenyl)-(2-(3-motolylureido)acethyl)amino)acetate (2.5 g) and adamantane-1-carbonylchloride (866 mg). Yield 6%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:13][C:14]([CH:17](OCC)[O:18]CC)=[CH:15][CH:16]=1.FC(F)(F)C(O)=O.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:13][C:14]([CH:17]=[O:18])=[CH:15][CH:16]=1
Reactant: CCOC(OCC)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
2.6 g of 6-bromo-4-(5-diethoxymethylthiophen-2-yl)quinazoline (compound in Production Example 380) was dissolved in 10 mL dichloromethane, then 5 mL trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 3 hours, neutralized by adding water and a sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated, whereby 2.07 g of the title compound was obtained as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10]O)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>O1CCCC1>[F:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:3]=1
Reactant: N#Cc1cc(CO)c(F)cc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#N)c(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17.6 %

Procedure:
To a solution (10 mL) of 4-fluoro-5-(hydroxymethyl)-2-(trifluoromethyl)benzonitrile (545 mg) and triethylamine (0.862 mL) in tetrahydrofuran was added dropwise methanesulfonyl chloride (0.289 mL) at 0° C. After the dropwise addition, the mixture was stirred at room temperature for 1.5 hr, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL) and sodium borohydride (400 mg) was added thereto. The reaction mixture was stirred for 1.5 hr and methanol (2.5 mL) was added thereto. The mixture was stirred for 30 min, and saturated aqueous sodium hydrogencarbonate was added thereto. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=15:1→1:1) to give the title compound as a yellow oil (yield: 89 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[NH2:11])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>C1C=CC=CC=1>[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=[N:11][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH2:22][CH2:21]1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(N(CCc2ccc(C)nc2)N=C2CCN(C)CC2)cc1

Procedure:
The crude N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine was dissolved in benzene (20 cm3) and 4 Å molecular sieves added (˜5 g), followed by 1-methylpiperidin-4-one (346 μL, 3.0 mmol). The reaction was heated to reflux for 2 hours, cooled, and filtered. Solvent was removed in vacuo to yield a crude orange oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][OH:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=[CH2:14].[I+].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1.[H-].[Na+]>[CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:15][C:13]([CH2:12][Cl:11])=[CH2:14])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CO)OCC
Reactant: C=C(CCl)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: C=C(CCl)COCP(=O)(OCC)OCC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a mixture of hydroxymethylphosphonic acid diethylester (0.84 g, 5 mmol), 1-chloro-2-chloromethyl-2-propene (0.95 g, 7.6 mmol) and tetrabutylammonium iodine (0.18 g, 0.5 mmol) in anhydrous tetrahydrofuran (10 ml), sodium hydride is added (0.24 g, 6 mmol 60% in oil) at 0° C. The mixture is stirred overnight at 20° C. The reaction mixture is hydrolyzed with a saturated solution of ammonium chloride, extracted with ethyl acetate and the title product is obtained by flash chromatography on silica gel (0.35 g, 27%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH:10]1[C:11]2[N:12]([C:20]3[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH3:14])=[CH:18][CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
To carbazole (5.0 g) in dimethylsulfoxide (DMSO) (50 mL) is added 4-fluoroacetophenone (3.5 g) and K2CO3 (10.4 g), and the mixture is stirred at 135° C. overnight. The mixture is poured into water to afford a precipitate, which is isolated by filtration and washed with water. The crude product thus obtained is further purified by recrystallization from TBME, giving the product as a light brown solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.71 (s, 3H), 7.32 (ddd, 2H), 7.41-7.50 (m, 4H), 7.72 (d, 2H), 8.15 (d, 2H), 8.21 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH:9]=[C:10]([C:11]([O:13]CC)=[O:12])[C:4]=2[O:3]1.[OH-].[Li+].CO.O1CCCC1>O>[CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:4]=2[O:3]1
Reactant: CCOC(=O)c1cc(-n2cnnn2)cc2c1OC(C)(C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(-n3cnnn3)cc(C(=O)O)c2O1
Yield: 82.8 %

Procedure:
A solution of ethyl 2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-carboxylate (676) (182 mg, 0.631 mmol), lithium hydroxide (106 mg, 2.53 mmol), methanol (1 mL), tetrahydrofuran (1 mL), and water (4 mL) was heated at 50° C. for 1 hour. The volatiles were removed in vacuo and 2N HCl was added. The white solid was collected by filtration washing with water to provide 2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-carboxylic acid (677) (136 mg, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[OH:15][C:16]12[CH2:26][CH:20]3[CH2:21][C:22]([OH:25])([CH2:24][C:18]([NH2:27])([CH2:19]3)[CH2:17]1)[CH2:23]2.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:27][C:18]34[CH2:24][C:22]5([OH:25])[CH2:21][CH:20]([CH2:26][C:16]([OH:15])([CH2:23]5)[CH2:17]3)[CH2:19]4)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnn2cc(Br)cc2c1NC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 80 mg, 0.291 mmol), 3,5-dihydroxyadamantan-1-amine (53.4 mg, 0.291 mmol) and DIPEA (0.104 mL, 0.583 mmol) in DMF (1 mL) was heated in microwave oven at 130° C. for 1.5 h. The reaction mixture was cooled to rt, water added (4 volumes) and the resulting mixture was stirred rapidly overnight. The solids were filtered and rinsed with water to afford the title compound as a yellow solid (72 mg, 56% yield). HPLC (condition 0): retention time=2.16 min; LCMS: 423.00 (M+2); 1H NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.01 (d, J=1.8 Hz, 1H), 6.23 (s, 2H), 2.52 (m, 1H), 2.14 (app dd, J=7.1 Hz, 4H), 2.01 (m, 2H), 1.82 (m, 2H), 1.72 (s, 4H).
Reaction SMILES: ClC(OCC)=O.C(N(CC)CC)C.[C:14]1([CH:20]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:26][CH:25]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC([O:47][NH2:48])(C)C>C1COCC1>[CH:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH:20]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27](/[CH:30]=[CH:31]/[C:32]([NH:48][OH:47])=[O:33])=[CH:28][CH:29]=2)=[O:22])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:41][CH:40]=1
Reactant: COC(C)(C)ON
Reactant: O=C(O)C=Cc1ccc(NC(=O)C(Cc2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(NC(=O)C(Cc2ccccc2)c2ccccc2)cc1)NO
Reaction time: 0.17 h

Procedure:
Ethyl chloroformate (1.26 mmol, 0.12 mL) and triethylamine (1.37 mmol, 0.19 mL) were added to a cooled (0° C.) solution of 3-[4-(2,3-Diphenylpropionylamino)phenyl]-2-propenoic acid (1.05 mmol, 0.39 g) in dry THF (10 mL), and the mixture was stirred for 10 min. The solid was filtered off, and O-(2-methoxy-2-propyl)hydroxylamine (3.15 mmol, 0.23 mL) was added to the filtrate. The solution was stirred for 15 min at 0° C., then was evaporated under reduced pressure, and the residue was diluted in methanol (10 mL). Amberlyst® 15 ion-exchange resin (105 mg) was added to the solution of the O-protected hydroxamate, and the mixture was stirred at room temperature for 1 h. After, the reaction was filtered and the filtrate was concentrated in vacuo to give the crude MC1895 which was purified by crystallization. 1H NMR (DMSO-d6) δ 3.05 (m, 1H, PhCH2), δ 3.60 (m, 1H, PhCH2), δ 3.75 (m, 1H, PhCHCO), δ 6.36 (d, 1H, PhCH═CHCOOEt), δ 7.15-7.70 (m, 15H, benzene protons and PhCH═CHCOOEt), δ 9.00 (s, 1H, OH), δ 10.23 (s, 1H, CONHPh), δ 10.85 (s, 1H, NHOH). Anal. C, H, N, O.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[OH:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16]([O:18][P:19]([CH2:24]OS(C1C=CC(Cl)=CC=1)(=O)=O)(=[O:23])[O:20][CH2:21][CH3:22])[CH3:17].O>CS(C)=O>[C:5]([O:13][C:11]([NH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][P:19](=[O:23])([O:18][CH2:16][CH3:17])[O:20][CH2:21][CH3:22])=[CH:7][CH:6]=1)=[O:12])([CH3:8])([CH3:6])[CH3:4]
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(Cl)cc1)OCC
Reactant: O=C(O)NCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOP(=O)(COc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC

Procedure:
A solution of 2-(4-hydroxyphenyl)ethylcarbamic acid, t-butyl ester1 (4.0 g, 16.9 mMol) in dry DMSO (37.5 ml) was cooled in an ice-bath and treated with sodium hydride (80% in mineral oil 0.557 g, 1.1 equiv) with stirring under argon according to the method described by Cornforth2. When effervescence ceased a solution of 4-chlorobenzenesulfonyloxymethylphosphonate diethyl ester (6.07 g, 1.05 equiv) in dry DMSO (110 ml) was added and the resulting pale yellow solution stirred at room temperature overnight. The mixture was then poured into water (550 ml) and extracted with diethyl ether/ethyl acetate (1:1, 3×150 ml) and finally ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting oil was purified by chromatography on silica gel with a gradient of 3:2 pentane:ethyl acetate rising to 100% ethyl acetate to give the title compound as a colourless viscous oil.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9](C(C)(C)C#N)=NC(C)(C)C#N.C1C=CC=CC=1.C(C1C=CC=CN=1)=C>CCCCCC>[CH:2]([C:3]1[CH:8]=[CH:7][N:9]=[CH:5][CH:4]=1)=[CH2:1].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C=Cc1ccccn1
Solvent: CCCCCC
Solvent: C=Cc1ccccc1
Solvent: c1ccccc1
Product: C=Cc1ccncc1

Procedure:
In a 200 ml three necked flask were charged 21 g of 4-vinylpyridine, 21 g of styrene and 0.1 g of azobisisobutyronitrile and 90 ml of benzene. The mixture was polymerized at 80° C. for 6 hrs under a nitrogen atmosphere. The reaction liquid was poured into a large amount of n-hexane to thereby obtain white precipitates. After filtering and drying, a white powder was obtained. The molar fraction of vinylpyridine in the polymer was 0.57 and the yield was 20%.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[N:10]([CH3:31])[C:11](=[O:30])[C:12]2([N:29]=1)[C:21]1[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=1)[S:15][CH:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13]2.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:9]1[N:10]([CH3:31])[C:11](=[O:30])[C:12]2([N:29]=1)[C:21]1[C:16](=[CH:17][CH:18]=[C:19]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[CH:20]=1)[S:15][CH:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Sc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Sc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 110 °C
Yield: 50.5 %

Procedure:
To a solution of 2-amino-6′-bromo-1-methyl-2′-phenylspiro[imidazole-4,4′-thiochroman]-5(1H)-one TFA salt (70 mg, 0.14 mmol), 3-cyanophenylboronic acid (51 mg, 0.34 mmol), and Cs2CO3 (250 mg) in 1,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl2(PPh3)2 (20 mg). Then the system is degassed by sweeping with N2. The tube is capped and heated to 110° C. for 30 min in a CEM microwave reactor. Solvent is removed in vacuo and the residue is purified by preparative HPLC to give 3-(2-amino-1-methyl-5-oxo-2′-phenyl-1,5-dihydrospiro-[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile (30 mg) as a TFA salt. MS ESI+ve m/z 425 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH3:17])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[CH3:20][C:21]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][N:16]([CH3:17])[C:23]([C:22]2[C:21]([CH3:20])=[N:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:27][CH:26]=2)=[O:25])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNC)cc1
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(C)C(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-[4-(2-methylamino-ethyl)-phenoxy]-propionic acid ethyl ester (example 88A]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[4-(2-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[CH:16][N:17]([C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[N:18]=2)[N:8]=[CH:9][C:10]=1[C:11](OCC)=[O:12])[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[CH:16][N:17]([C:19]([O:22][CH3:23])([CH3:20])[CH3:21])[N:18]=2)[N:8]=[CH:9][C:10]=1[CH2:11][OH:12])[CH:2]=[CH2:3]
Reactant: C=CCNc1c(C(=O)OCC)cnc2cn(C(C)(C)OC)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCNc1c(CO)cnc2cn(C(C)(C)OC)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
A solution of ethyl 7-allylamino-2-(2-methoxy-2-propyl)-2H-pyrazolo[4,3-b]pyridine-6-carboxylate (2.38 g, 7.5 mmol) in dry THF (tetrahydrofuran) (25 ml) was added dropwise to an ice-cooled suspension of lithium aluminium hydride (285 mg, 7.5 mmol) in dry THF (15 ml). The mixture was stirred at room temperature, under nitrogen, for 24 h, then water (0.3 ml), 10% sodium hydroxide solution (0.3 ml) and water (0.85 ml) were added sequentially. The mixture was filtered through Kieselguhr, the solvent was evaporated in vacuo, and the residual solid was recrystallised from ethyl acetate to give the title compound as needles (1.87 g, 90%), m.p. 152°-154° C. Found: C, 60.58; H, 7.21; N, 20.26C14H20N4O2 requires C, 60.84; H, 7.29; N, 20.27%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10](SC)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=O)C=1.S(=O)(O)[O-].[Na+].[N:45]1([CH2:51][CH2:52][OH:53])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.[H-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])=[C:12]([CH3:26])[N:11]=[C:10]([O:53][CH2:52][CH2:51][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Reactant: OCCN1CCCCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [H-]
Solvent: ClCCl
Product: Cc1nc(OCCN2CCCCC2)nc(-c2cccc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
185 mg (0.254 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of dichloromethane. 87.7 mg (0.508 mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at 0° C. and stirred at the same temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite solution was added thereto at the same temperature and stirred for 30 minutes heating to room temperature. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of DMF. Alkoxide prepared from 146 mg (1.13 mmol) of 1-piperidine ethanol and 45.2 mg (1.13 mmol) of sodium hydride (60% oily substance) was added at 0° C. and stirred heating to room temperature for 1 hour. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound.