Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].CN(C)P(N(C)C)(N(C)C)=O.[CH2:32](Br)[CH:33]=[C:34]([CH2:36][CH2:37][CH:38]=[C:39]([CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])[CH3:40])[CH3:35]>C1COCC1>[CH3:35]/[C:34](/[CH2:36][CH2:37]/[CH:38]=[C:39](\[CH3:40])/[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])=[CH:33]\[CH2:32][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 9.60 ml (68.5 mmol, 1.5 eq.) of diisopropylamine in 100 ml of THF at -78° C. under argon was added 28.2 ml (45.0 mmol, 1.0 eq.) of 1.6M n-butyllithium in hexanes over 20 minutes. After warming to 0° C. for 15 minutes, the solution was recooled to -78° C. and 6.05 ml (45 mmol, 1.0 eq) of t-butyl acetate was added over 20 minutes. After an additional 15 minutes, 16.0 ml (92 mmol, 2.05 eq.) of hexamethylphosphoramide (HMPA) was added, followed by a solution of 12.53 g (45.0 mmol) of Part A(1) farnesyl bromide in 100 ml of THF over 20 minutes. The reaction was stirred at -78° C. for 2.5 hours, quenched with saturated NH4Cl and allowed to warm to room temperature. After diluting with 400 ml of ethyl acetate, the mixture was washed with four 100 ml portions of water, and 200 ml of brine, dried over MgSO4 and evaporated to provide 12.96 g of crude product as a yellow oil. Purification by flash chromatography on 1 kg of silica gel, eluted with 1:9 ethyl acetate:petroleum ether afforded 9.39 g (65%) of title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][OH:10]>[Pt].CC(C)=O>[C@H:3]12[CH2:2][O:1][C:9](=[O:10])[C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: OCC1CCCCC1CO
Agent: [Pt]
Solvent: CC(C)=O
Product: O=C1OC[C@@H]2CCCC[C@H]12
Temperature: 0 °C
Yield: 92 %

Procedure:
There were weighed out 1,2-bis(hydroxymethyl)cyclohexane (7, meso compound) (144 mg, 1.00 mmol) and (S)-(−)-3,3,5,5-tetramethyl-4H-dinaphtho[2,1-c:1′,2′-e]-azepin-N-oxyl (3.0 mg, 1.00 mmol). Then, 2 ml of acetone was added to obtain a uniform solution. Two platinum electrodes (1.5×1.0 cm ) were applied to the solution which was then subjected to an electrolytic oxidation reaction for 4 hours while being vigorously stirred at 0° C. and maintaining the current at 30 mA (quantity of electricity being 4.5 F/mol). After completion of reaction, silica gel was filtered off from the reaction mixture, extraction was effected with 5 ml of acetone and acetone was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane-7/1), giving (1R,6S)-8-oxabicyclo[4.3.0]nonan-7-one (8) (cis lactone) (122 mg, yield 92%, optical purity 85%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:20]1[N:25]=[CH:24][C:23]2=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[N:22]2[N:21]=1)=O>>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH:16][C:20]3[N:25]=[CH:24][C:23]4=[CH:26][CH:27]=[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[N:22]4[N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3NS(C)(=O)=O)n2n1
Product: CS(=O)(=O)Nc1ccccc1-c1ccc2cnc(Nc3cccc(OCCN4CCOCC4)c3)nn12

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(2-Morpholin-4-yl-ethoxy)-phenylamine and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide. 1H-NMR (DMSO) δ 9.9 (br s, 1H), 9.6 (s, 1H), 9 (s, 1H), 8.8 (s, 1H), 7.7 (d, J=8.0 Hz, 1H), 7.6 (m, 2H), 7.5 (m, 1H), 7.4 (brs, 1H), 7.2 (m, 1H), 7.1 (t, J=8.0 Hz, 1H), 7 (s, 2H), 6.6 (d, J=7.2 Hz, 1H), 4.1-3 (m, 12H), 2.7 (s, 3H); LC/MS (ESI+): 509 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1CCO.CCCCC.C([Li])(C)(C)C.C([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=O)=[CH:25][C:24]=1O)=O.[Cl-].[NH4+]>O1CCCC1.O>[C:2]1([CH:27]([C:26]2[CH:25]=[CH:24][CH:23]=[CH:32][CH:31]=2)[OH:29])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccccc1Br
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.8 %

Procedure:
To a solution of 2-(bromophenyl)ethylalcohol (1.7 g) in tetrahydrofuran (100 mL) was added 1.45 mol/L tert-butyllithium n-pentane solution (12.6 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 10 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.50 g) in tetrahydrofuran (10 mL) was added to the reaction mixture. After the reaction mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give a diphenylmethanol compound (0.28 g). The obtained diphenylmethanol compound (0.28 g) was dissolved in methanol (5 mL), and 10% palladium-carbon powder (0.14 g) was added to the solution. After the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]benzoate (0.26 g).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH:7]([N:10]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[N:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:11]1=[O:32])[CH2:8][CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[C:11](=[O:32])[N:10]([CH:7]([CH2:8][CH3:9])[C:6]([OH:33])=[O:5])[C:14]=2[CH:15]=1)#[N:20]
Reactant: CCC(C(=O)OC(C)(C)C)n1c(=O)n(S(=O)(=O)c2ccc(OC)cc2)c2ccc(C#N)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(=O)O)n1c(=O)n(S(=O)(=O)c2ccc(OC)cc2)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A stirred solution of 2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydrobenzoimidazol-1-yl]-butyric acid tert-butyl ester (34 mg, 0.07 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×) to afford 2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydrobenzoimidazol-1-yl]-butyric acid (29 mg, 99%) as a white solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O[C:6]1[CH:19]=[C:18]2[C:9]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15](C=O)[C:16](=[O:20])[C:17]=32)=[CH:8][CH:7]=1.[C:23](O)(=O)[CH2:24][C:25]([OH:27])=[O:26]>N1C=CC=CC=1>[C:1]([O:4][C:6]1[CH:19]=[C:18]2[C:9]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([C:24](=[CH2:23])[C:25]([OH:27])=[O:26])[C:16](=[O:20])[C:17]=32)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1coc2ccc3ccc(O)cc3c2c1=O
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: C=C(C(=O)O)c1coc2ccc3ccc(OC(C)=O)cc3c2c1=O

Procedure:
Thus, Compound 5 is refluxed with malonic acid in pyridine to obtain [9-(acetyloxy)-1-oxo-1H-naphtho[2,1-b]pyran-2-yl]-2-propenoic acid, compound 7. Additionally, Compound 6 may be refluxed in a similar fashion with malonic acid in pyridine to obtain [9-hydroxy-1-oxo-1H-naphtho[2,1-b]pyran-2-yl]-2-propenoic acid, Compound 7A.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=3)=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: OCc1cccc(F)c1
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 2e), the alkylation of (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 2c)] with 3-fluorobenzylalcohol yields the (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=344 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:25][C:24](=[O:26])[CH2:23][C:22](=[O:27])[O:21]2)[CH:13]=1)([CH3:11])[CH3:10])(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C(Cl)Cl>C1(C)C=CC=CC=1>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:7][CH2:8][C:9]([C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][C:20]2([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:21][C:22](=[O:27])[CH2:23][C:24](=[O:26])[CH2:25]2)[CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1

Procedure:
(2-{3-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (1.80 g, 3.94 mmol), was stirred with 30% TFA/CH2Cl2 (30 mL), for 2 h. The reaction was diluted with Toluene (30 mL) and stripped of all solvents. The crude product was used without further purification. Yield 3.22 g.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][O:5]1)#N.[OH-:9].[Na+].C[OH:12]>O>[O:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][C:1]([OH:12])=[O:9]
Reactant: N#CCC1CCCO1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CC1CCCO1

Procedure:
A solution of 90 g. (0.81 mole) 2-cyanomethyltetrahydrofuran, 130 g. (3.2 mole) sodium hydroxide, 250 ml. methanol and 300 ml. water was heated at reflux for 20 hours. The reaction mixture was evaporated in vacuo, the residue taken up in chloroform and acidified to pH 5 with 6N hydrochloric acid. The organic layer was separated, the aqueous phase extracted with chloroform, the combined extracts dried (MgSO4) and the solvent evaporated to give 62 g. of crude acid. Distillation afforded 52.6 g. of product, B.P. 110° C. (2 mm.). 1H--NMR (CDCl3) ppm (delta): 2.50 (d, 2H, CH2COOH), 11.10 (s, 1H, COOH).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:7]1[C:12](=O)[C:11](Cl)=[C:10](Cl)[C:9](=O)[C:8]=1Cl>C1(C)C=CC=CC=1>[C:7]1([C:2]2[O:1][C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]3[C:3]=2[CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:2]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: c1ccoc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3c(-c4ccccc4)oc(-c4ccccc4)c3cc2-c2ccccc2)cc1

Procedure:
Next, the dihydro-compound of furan and tetrachloro-p-benzoquinone (chloranyl) in toluene were heated under reflux to effect dehydrogenation, yielding 1,3,5,6-tetraphenylisobenzofuran.
Reaction SMILES: [CH3:1][N:2](C)C(Cl)=O.[Br:7][C:8]1[C:9]([Cl:15])=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1.C[Si](C#N)(C)C>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:1]#[N:2])=[N:10][C:9]=1[Cl:15]
Reactant: [O-][n+]1cccc(Br)c1Cl
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: N#Cc1ccc(Br)c(Cl)n1

Procedure:
The reaction was also performed using the acylating agent dimethylcarbamoyl chloride. A solution of dimethylcarbamoyl chloride (12.9 mL, 0.14 mol) in dichloromethane (23 mL) was added drop-wise to a stirred solution of 3-bromo-2-chloropyridine 1-oxide (C27) (11.23 g, 53.9 mmol) and trimethylsilyl cyanide (17.5 mL, 0.14 mol) in dichloromethane (200 mL). The reaction mixture was heated under reflux for 3 days, then diluted with dichloromethane (450 mL) and washed with saturated aqueous sodium bicarbonate solution (2×200 mL), then with water (200 mL), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 15% to 20% ethyl acetate in heptane) provided the title compound, contaminated with dimethylcarbamoyl cyanide (12.73 g, 100%) as an off-white solid. The impurity was reduced by repeatedly washing with aqueous sodium hydroxide solution (2 N) and a second chromatography on silica gel. Although the impurity could not be completely removed, the material was used in the next step without any detrimental effects. Yield: 7.83 g, 36.0 mmol, 67%. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.8 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H).
Reaction SMILES: Cl.[N+:2]([C:5]1(OCC)[CH:10]=[CH:9][C:8](N)=[CH:7][CH2:6]1)([O-:4])=[O:3].[C:15]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[C:22]([OH:24])=O)([CH3:18])([CH3:17])[CH3:16].[CH2:33]([N:35](CC)CC)[CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:30][C:29]([C:26]1[CH:25]=[C:21]([CH:20]=[C:19]([C:15]([CH3:17])([CH3:16])[CH3:18])[C:27]=1[OH:28])[C:22]([NH:35][CH2:33][CH2:34][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[O:24])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCN(CC)CC
Reactant: CCOC1([N+](=O)[O-])C=CC(N)=CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
2.02 g (10 mmoles) of 4-nitrophenetylamine hydrochloride, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxy-benzoic acid, 1.38 ml (10 mmoles) of triethylamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 100 ml flask containing 20 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered out and rinsed with ethyl acetate. After concentration of the filtrate under reduced pressure, the residue is precipitated from diethyl ether. The solid is recovered by filtration and rinsed with diethyl ether. A white powder is obtained with a yield of 73%. Melting point: 204-206° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH:18]3[CH2:20][CH2:19]3)=O)=[CH:12][CH:11]=2)[N:3]=[CH:2]1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=2)[N:3]=[CH:2]1
Reactant: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCCCc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
0.8 mmol of cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl ketone (Example 61), 4 mmol of hydrazine hydrate and 3.2 mmol of KOH in 30 ml of triethylene glycol are brought to reflux for 2 hours. The solvent is evaporated off under reduced pressure, and the crude product is extracted with dichloromethane and purified by rotatory chromatography (eluent:dichloromethane/methanol (99:1)-(90:10), ammoniacal atmosphere). The product is crystallized in the form of hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[C:9]#[N:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.CCN(CC)CC.O>C(#N)C>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:11][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]#[N:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: N#CC(O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C#N)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
2-(2-chlorophenyl)-2-hydroxyacetonitrile (16.8 g, 0.1 mol) and 4-toluene sulfonyl chloride (21 g, 0.11 mol) was dissolved in acetonitrile (80 mL) in a suitable reaction flask, and Et3N (20 g, 0.2 mol) was added to the reaction dropwise at 0-25° C. Then the solution was stirred at room temperature for 5 h and afterwards refluxed until the reaction was completed by TLC monitoring. The acetonitrile was recovered and reaction mixture was diluted by water and extracted with butyl acetate. The organic layer was washed repeatedly with water and the butyl acetate was removed under reduced pressure giving the target product (30 g, yield 93.75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([O:15]C3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.FC1C=CC(CC(N=C=O)=O)=CC=1.COC1C=CC(CNC2N=CN=C(O[C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:74]([NH:76][C:77](=[O:86])[CH2:78][C:79]4[CH:84]=[CH:83][C:82]([F:85])=[CH:81][CH:80]=4)=[O:75])=[CH:69][C:68]=3[F:87])C=2)=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([O:15][C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:74]([NH:76][C:77](=[O:86])[CH2:78][C:79]4[CH:84]=[CH:83][C:82]([F:85])=[CH:81][CH:80]=4)=[O:75])=[CH:69][C:68]=3[F:87])[CH:12]=[CH:11][N:10]=2)=[CH:37][CH:38]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of N-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyrimidin-2-amine (Compound C of Example 14, 34 mg, 0.10 mmol) in THF (1 ml) was treated with 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.31 mL, 0.11 mmol) and the mixture stirred at RT for 1 h. The mixture was concentrated in vacuo and the solid obtained was triturated first with 3:1 isopropyl ether/EtOAc and then CH2Cl2 to give the title compound (32 mg, 62%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.26 (s, 1H), 8.15 (s, 1H), 7.76 (d, 1H, J=12.6 Hz), 7.61 (dd, 3H, J=9.1, 5.0 Hz), 7.29 (s, 2H), 7.31-7.21 (m, 3H), 6.81 (s, 3H), 6.24 (s, 1H), 4.32 (s, 1H), 3.96 (s, 1H), 3.68 (s, 3H), 3.48 (s, 2H); MS(ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 3-amino-4-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-4-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C18H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+]351.9 & 353.9.
Reaction SMILES: [CH:1](=[N:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(COC)OC>[CH3:13][N:12]([CH3:14])[S:9]([N:8]1[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][N:25]=[CH:24]1)(=[O:11])=[O:10]
Reactant: CN(C)S(=O)(=O)N=Cc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: CN(C)S(=O)(=O)n1cncc1-c1ccccc1

Procedure:
N-Benzylidene-N',N'-dimethylsulphamide (6.36 g) was stirred with p-toluenesulphonylmethyl isocyanide (9.75 g ) and potassium carbonate (8.28 g) in methanol and dimethoxyethane for 18 hours. The mixture was filtered and the filtrate evaporated and recrystallised from ethyl acetate/hexane to give crude 1-dimethylsulphamoyl-5-phenylimidazole.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)[S:11][C:4]=12.[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]3[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=3)[S:11][C:4]=12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CNc1ccnc2cc(-c3cn(C)cn3)sc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2cc(-c3cn(C)cn3)sc12
Temperature: 85 °C
Yield: 18.8 %

Procedure:
A stirred suspension of 344 (500 mg, ˜2 mmol), 3,4-difluoronitrobenzene (795 mg, 5 mmol) and cesium carbonate (1.63 g, 5 mmol) in anhydrous DMF (50 ml) was heated at 85° C. under nitrogen for 7 h. The temperature was allowed to cool down to room temperature. The reaction mixture was poured into water, and extracted with dichloromethane. The combined organic phase was concentrated and directly purified twice by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2: 5/95 to 10/90) to afford title compound 345 (144 mg, 19% yield) as a sticky yellow solid. MS (m/z): 384.0 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)C.[ClH:29]>O1CCOCC1>[ClH:29].[N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:20]([F:23])([F:21])[F:22])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cnc(N2CCCC2)cc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1cnc(N2CCCC2)cc1C(F)(F)F
Reaction time: 5 h

Procedure:
A solution of 1 g (3.02 mmol) of 6-(pyrrolidin-1-yl)-4-trifluoromethyl-3-(tert-butoxycarbonylamino)pyridine, prepared in step 11.3, in 11 ml of 4N hydrochloric acid in dioxane is stirred for 5 hours at reflux. 200 ml of ethyl ether are subsequently added to the cooled reaction mixture. 0.8 g of a precipitate is recovered by filtration.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:5]([CH2:13][OH:14])[CH:4]=1)[NH2:2].C(N(CC)CC)C.[CH:22]1([C:28](=O)[CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C(O)C>[CH:32]1([C:30]2[CH:29]=[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:1]([C:3]3[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:10])=[O:11])=[C:5]([CH2:13][OH:14])[CH:4]=3)[N:2]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NNc1ccc(S(N)(=O)=O)c(CO)c1
Reactant: O=C(CC(=O)C1CCCCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C3CCCCC3)cc2-c2ccccc2)cc1CO
Temperature: 100 °C
Reaction time: 72 h
Yield: 15.6 %

Procedure:
To a suspension of 4-hydrazinyl-2-(hydroxymethyl)benzenesulfonamide (224 mg, 0.884 mmol) in ethanol (4.0 mL), triethylamine (246 μL, 1.77 mmol) and 1-cyclohexyl-3-phenylpropan-1,3-dione (185 mg, 0.803 mmol) were added, and the obtained solution was stirred at 100° C. for 72 hours. Water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/chloroform/acetone) to obtain the title compound (51.5 mg, 0.125 mmol, 16%) as a white amorphous product.