Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=O)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].[OH-].[Na+].C.Cl>O.O1CCOCC1.N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=[S:15])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc(NC(C)=O)cc1C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(NC(C)=S)cc1C

Procedure:
185 g of 2-methyl-4-acetamino-anisole (prepared by procedures described by M. Heidelberg and W. A. Jacobs in J.A.C.S. 41 (1919) p. 1453), 100 ml of pyridine and 250 ml of anhydrous dioxane were poured into a 1 l. multi-neck flask mounted on an oil bath whose temperature was 100° C. After complete dissolution, 130 g of P2S5 were added thereto in small portions under stirring; after the addition, the solution thus obtained was stirred for another 45 minutes by maintaining the conditions of the reaction temperature. The reaction mixture was poured into a 5 l. of a very cold water solution of 45 g of NaOH; animal charcoal was added thereto and the whole stirred for 1 hour. After filtration, the solution was poured into a Keller flask, provided with a stirrer and externally cooled, cautiously acidified with concentrated HCl to pH=4-5, keeping the temperature lower than +5° C. After approximately 1 hour of stirring, the product, thus separated, was filtered with a Buchner and washed with water. The raw product was crystallized many times from ligroin in the presence of animal charcoal to reach a melting point of 88.5°-89° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[Cl:25])(=[O:4])=[O:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:26]([NH:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:7][C:6]=1[Cl:25])(=[O:3])=[O:4])(=[O:28])[CH3:27]
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)c(Cl)c2)=C(c2ccccc2)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Cl

Procedure:
150 mg of 5-{4-(aminosulfonyl)-3-chlorophenyl}-2,2-dimethyl-4-phenyl-3(2furanone (Example 367) in 10 ml dichloromethane was reacted with 0.3 ml acetic anhydride in the presence of 0.5 ml triethylamine and 15 mg of 4-(N,N-dimethylamino)pyridine at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, which was followed by extraction with 30 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and then was purified by column chromatography (hexane/ethylacetate 2:1) to afford 113 mg of 5-[4-{(acetylamino)sulfonyl}-3-chlorophenyl]-2,2-dimethyl-4-phenyl-3(2H)-furanone as a solid. mp: 194-195° C. NMR: δ1.57 (s, 6H), 2.10 (s, 3H), 7.27 (m, 2H), 7.40 (m, 3H), 7.68 (dd, J=8.4, 1.8 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H), 8.45 (br s, 1H). IR (cm−1): 3195, 3104, 1698, 1377, 1164.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N:10]([O:12]C(C)(C)C)=[O:11].ON1C(=O)C2=CC=CC=C2C1=O.C(C1C=CC=CC=1)(C)=C.OC(C1C=CC=CC=1)(C)C>C(O)(=O)C>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([N+:10]([O-:12])=[O:11])[CH3:3]
Reactant: CC(C)c1ccccc1
Reactant: CC(C)(C)ON=O
Agent: C=C(C)c1ccccc1
Agent: CC(C)(O)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Product: CC(C)(c1ccccc1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Isopropylbenzene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that isopropenylbenzene, (1-hydroxy-1-methylethyl)benzene, and (1-methyl-1-nitroethyl)benzene were formed in yields of 60%, 6%, and 7%, respectively.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:51][C:52](=[O:58])[CH2:53][CH2:54][C:55](O)=[O:56]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:55](=[O:56])[CH2:54][CH2:53][C:52]([NH2:51])=[O:58])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)CCC(=O)O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)CCC(N)=O)C2
Temperature: 25 °C
Yield: 20.8 %

Procedure:
To a stirred solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 3) (100 mg, 0.25 mmol) and N-methylmorpholine (56 μL, 0.5 mmol) in DMF (5 ml, anhydrous) was added EDC (53 mg, 0.28 mmol), HOBT (38 mg, 0.28 mmol), and 4-amino-4-oxobutanoic acid (29.7 mg, 0.25 mmol). The reaction mixture was stirred at room temperature until analysis by LCMS deemed reaction complete. Solvent was then removed in vacuo. Purified by prep. HPLC (high pH) to afford a white solid (25.7 mg, 0.052 mmol, 21%).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([I:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.FC1C(F)=CC=CC=1N.ClC1C=C[C:26]([O:29]C)=CC=1N>>[I:11][C:8]1[S:9][C:10]2[CH:2]=[CH:3][C:4]([O:29][CH3:26])=[CH:5][C:6]=2[N:7]=1
Reactant: Fc1cccc2nc(I)sc12
Reactant: COc1ccc(Cl)c(N)c1
Agent: Nc1cccc(F)c1F
Product: COc1ccc2sc(I)nc2c1

Procedure:
The title compound was prepared following the route for 7-fluoro-2-iodo-1,3-benzothiazole from 2,3-difluoroaniline, starting from 2-chloro-5-methoxyaniline and conducting the first step at 150° C. for 16 h.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(-c2ccc(C)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A solution of 7.31 g of Methyl 4'-methylbiphenyl-3-carboxylate, 5.75 g of N-bromosuccinimide, 0.125 g of azo(bisisobutyronitrile), and 500 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature the resulting suspension was filtered and then concentrated in vacuo to provide 9.90 g of crude methyl 4'-bromomethylbiphenyl-3-carboxylate which was used in a subsequent reaction without further purification; NMR (200 MHz, CDCl3): δ 8.28 (s, 1H); 8.05 (d, 1H); 7.79 (d, 1H); 7.67-7.48 (m, 5H); 4.55 (s, 2H); 3.98 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][CH:5]([C:7](=[CH2:11])[C:8](=[O:10])[CH3:9])[C:4]1([CH3:13])[CH3:12])C.[C-:14]#[N:15].C([Al+]CC)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:8]([CH:7]1[CH:11]([C:14]#[N:15])[CH2:1][CH:3]2[CH2:6][CH:5]1[C:4]2([CH3:12])[CH3:13])(=[O:10])[CH3:9]
Reactant: C=C(C(C)=O)C1CC(CC)C1(C)C
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)C1C(C#N)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3-Ethyl-2,2-dimethyl-cyclobutyl)-but-3-en-2-one (568 mg, 3.46 mmol) was dissolved in benzene (20 ml) under an atmosphere of dry N2. To the solution was added a 1.0 M solution of diethylaluminum cyanide (5.0 ml) in toluene. After stirring at ambient temperature for 30 minutes, a 10% aqueous solution of potassium sodium tartrate (20 ml) was added to the reaction. After stirring at ambient temperature for 30 minutes, the reaction was partitioned between CH2Cl2 and 0.1 N aqueous sodium hydroxide (NaOH). The CH2Cl2 layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give 551 mg of the titled compound as an oil: 1H NMR (CDCl3)δ 3.99 (dt, J=4.3, 11.0 Hz, 1H), 3.14 (dd, J=3.1, 4.6 Hz, 1H), 2.62 (m, 1H), 2.53 (m, 1H), 2.41 (m, 1H), 2.22 (m, 1H), 2.17 (s, 3H), 2.01 (m, 1H), 1.44 (d, J=10.6 Hz, 1H), 1.22 (s, 3H), 0.64 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[C:29]([OH:31])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:32][OH:33]>>[OH:33][NH:32][C:29]([C@H:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[NH:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:15][CH:16]=1)(=[O:22])=[O:21])=[O:31]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 43 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 321.4 mg (0.73 mmol) of (1S,2R)-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid with hydroxylamine provided 139.5 mg of (1S,2R)-N-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide with 43% yield. MS: 456.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([C:10]2[C:11]([F:20])=[CH:12][C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]=3[CH:19]=2)[C:3]1=[O:21].[H-].[Na+].Cl[CH2:25][C:26]([NH2:28])=[O:27].O>CN(C)C=O>[C:26]([CH2:25][N:15]1[C:14]2[CH:19]=[C:10]([N:4]3[C:5](=[O:9])[CH:6]=[C:7]([CH3:8])[N:2]([CH3:1])[C:3]3=[O:21])[C:11]([F:20])=[CH:12][C:13]=2[S:17][C:16]1=[O:18])(=[O:27])[NH2:28]
Reactant: Cc1cc(=O)n(-c2cc3[nH]c(=O)sc3cc2F)c(=O)n1C
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(=O)n(-c2cc3c(cc2F)sc(=O)n3CC(N)=O)c(=O)n1C
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3.07 g of 1,6-dimethyl-3-(6-fluoro-2-oxo-5-benzothiazolinyl)-2,4(1H,3H)-pyrimidinedione (see Example 79) and 0.48 g of a 55% sodium hydride dispersion are stirred at 25° C. for 1 hour in 50 ml of absolute dimethylformamide. Subsequently, 1.02 g of chloroacetamide are added and the mixture is stirred at 50° C. for 6 hours. The reaction mixture is cooled and treated with 400 ml of water. The precipitated product is filtered off under suction, washed with water and the filter cake is suspended in 200 ml of ethyl acetate at 60° C. The suspension is concentrated to about 50 ml, cooled to 25° C., the solid is filtered off under suction and dried at 50° C. In this manner there is obtained 3-(3-carbamoylmethyl-6-fluoro-2-oxo-5-benzothiazolinyl)-1,6-dimethyl-2,4(1H,3H)-pyrimidinedione, m.p.>260° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH:12]=[O:13])[CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH:12]([OH:13])[CH3:14])[CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: C[Mg+]
Reactant: O=CC1CCc2c(Cl)ncnc2C1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C1CCc2c(Cl)ncnc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a cooled (0° C.) solution of 4-chloro-5,6,7,8-tetrahydroquinazoline-7-carbaldehyde (0.10 g, 0.51 mmol) in THF (5 mL) was added a solution of MeMgBr (3.0 M in ethyl ether, 0.40 mL, 1.2 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes and then partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography provided 1-(4-chloro-5,6,7,8-tetrahydroquinazolin-7-yl)ethanol (0.09 g, 83% yield) as a waxy solid. MS (ES) for C10H13ClN2O: 213 (MH+).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:8][O:9][Si](C(C)(C)C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH:1]1([CH2:6][C@H:7]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCC1

Procedure:
tert-Butyl (S)-3-cyclopentyl-1-(t-butyldimethylsilyloxy)propan-2-ylcarbamate (2.9 g, 8.1 mmol) was stirred with 1 M Bu4NF in THF (24.3 mL) at 0° C. for 1 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give crude tert-butyl (S)-3-cyclopentyl-1-hydroxypropan-2-ylcarbamate that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHZ) δ 1.09 (m, 2 H), 1.44 (s, 9 H), 1.50 (m, 3 H), 1.60 (m, 3 H), 1.81 (m, 3 H), 3.52 (m, 1 H), 3.68 (m, 2 H), 4.60 (brs, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([CH3:20])[C:13]3=[O:21])[CH:8]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]([C:35](O)=[O:36])=[CH:33][C:32]([S:38]([CH3:41])(=[O:40])=[O:39])=[N:31]2)=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]([C:35]([NH:2][C:3]3[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][N:14]([CH3:20])[C:13]5=[O:21])[CH:8]=3)=[O:36])=[CH:33][C:32]([S:38]([CH3:41])(=[O:39])=[O:40])=[N:31]2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: CS(=O)(=O)c1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(S(C)(=O)=O)nn2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 20 h
Yield: 20.5 %

Procedure:
6-(5-Amino-2-methyl-phenylamino)-3-methyl-3H-quinazolin-4-one HCl salt (138 mg, 0.49 mmol) was dissolved in DMF (2 mL) with 2-(4-fluoro-phenyl)-5-methanesulfonyl-2H-pyrazole-3-carboxylic acid (140 mg, 0.49 mmol) at RT. HATU (186 mg, 0.54 mmol) was added, followed by DIEA (0.21 mL, 1.2 mmol). The mixture was stirred for 20 h. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 55 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 547.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[CH:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14]1.[Br:24]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:24][C:19]#[C:18][C:16]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14][N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C#CBr)c(C(F)(F)F)n2)c(Cl)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)4ethynyl-3-trifluoromethylpyrazole (3.1 g) in acetone (25 ml) was added N-bromosuccinimide (1.4 g) and silver nitrate (0. 14 g). Stirring was continued at room temperature for 2 hours. The reaction mixture was evaporated and the residue partitioned between ether and water. The organic layer was separated, dried and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane and then dichloromethane: hexane (1:1). Combination and evaporation of appropriate fractions, followed by crystallisation from hexane, gave the title compound as a white solid m.p. 92-94° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:27][CH:26]=2)([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1.C(OCC)(=O)C>CS(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:27][CH:26]=2)([CH3:24])[CH2:20][CH2:21][CH:22]=[O:23])=[CH:15][CH:14]=1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(CCC=O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
To a solution in DMSO (20 mL) of 4,4-bis(4-(2-quinolylmethoxy)phenyl)-pentan-1-ol (410 mg, 0.74 mmol), prepared as in Example 4, and 1,3-dicyclo-hexylcarbodiimnide (515 mg, 2.5 mmol) was added aqueous IM phosophoric acid (0.5 mL) and the resulting mixture was stirred at room temperature for 4 hours. Ethyl acetate (80 mL) was added and dicyclohexylurea was filtered off. The filtrate was washed with water and brine dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (methylene chloride-ethyl acetate 9:1) to afford 280 mg of 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanal.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH2:14]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CNc1nc(Cl)nc2ccccc12

Procedure:
Prepared as in Example 38 from 2,4-dichloroquinazoline and methylamine. 1H NMR (400 MHz, DMSO-d6) δ 2.98 (d, J=4.4 Hz, 3H), 7.53-7.49 (m, 1H), 7.61-7.58 (m, 1H), 7.79-7.75 (m, 1H), 88.19-8.17 (m, 1H), 78 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[C:13]=3[C:28]=2[CH3:29])=O)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]3[O:16][C:15]([CH3:17])([CH3:18])[CH:14]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][CH:20]=4)[C:13]=3[C:28]=2[CH3:29])=[CH:32][CH:33]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NCc1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 37 %

Procedure:
By using 4-chloro-N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 37%. Melting point: 93-94° C. (Methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:15]([CH2:16][CH2:17][C:18]#[N:19])=[CH:14][C:13]([CH2:20][OH:21])=[CH:12][N:11]=1.N1C=CN=C1.[C:27]([Si:31]([CH3:34])([CH3:33])Cl)([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>CN(C=O)C>[Si:31]([O:21][CH2:20][C:13]1[CH:14]=[C:15]([CH2:16][CH2:17][C:18]#[N:19])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[N:11][CH:12]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CCC#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2CCC#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 3-(2-(2-fluoro-5-methoxyphenyl)-5-(hydroxymethyl)pyridin-3-yl)propanenitrile (424 mg) and imidazole (155 mg) in DMF (10 mL) was added tert-butyldimethylchlorosilane (265 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (524 mg) as a colorless oil.
Reaction SMILES: C(OC([NH:8][CH:9]([C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])[C:10]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=O)(C)(C)C.O1CCOCC1>Cl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][S:13][C:10]([CH3:11])([CH3:12])[CH:9]([NH2:8])[C:23]([N:25]2[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[CH:16][CH:17]=1
Reactant: COc1ccc(CSC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)N2CCC(C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CSC(C)(C)C(N)C(=O)N2CCC(C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.8 %

Procedure:
Compound (29) (36.0 g; 80.0 mmol) was dissolved in a 4N hydrogen chloride solution in dioxane (400 ml; 1600 mmol) under cooling, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and washed with petroleum ether by decantation, followed by concentration to give Compound (30) (HCl salt) (30.8 g; yield, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8]>C(O)C>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:4]([CH2:3][CH2:2][CH2:7][CH2:6][CH3:5])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Solvent: CCO
Product: CCCCCc1nc2cc(-c3ccccc3C#N)ccc2[nH]1
Reaction time: 2.5 h
Yield: 160.7 %

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (4.3 mmoles, 0.9 g) and ethyl hexanoamidate hydrochloride were dissolved in 20 ml ethanol and stirred for 2.5 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic phase was dried and concentrated. The residue was chromatographed on silica gel eluted with 1:1 ethylacetate/hexane to yield 1.0 g of 5-(2-Cyanophenyl)-2-pentyl-1H-benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[O:10]C=CC=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>CC(C)=O.O>[NH2:1][C:2]1[C:3]([C:9]([OH:10])=[O:15])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Nc1ccc(Cl)nc1-c1ccco1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1ccc(Cl)nc1C(=O)O
Temperature: 0 °C
Yield: 67.7 %

Procedure:
3-Amino-6-chloro-2-(2-furanyl)pyridine (1.06 g) was dissolved in acetone (25 mL) and cooled in an ice bath to 0° C. A solution prepared of potassium permanganate (2.57 g) in water (40 mL) was added drop wise to this solution. After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for hours. The mixture was cooled again to 0° C. and a second portion of potassium permanganate (858 mg) in water (15 mL) was added and the cool bath removed. After stirring for 2 hours, the reaction mixture was filtered through a pad of celite, the filter cake was washed carefully with water, methanol and ethyl acetate and concentrated to approx. 20 mL on a rotary evaporator. 2N Sodium hydroxide solution was added to adjust the pH-value to −12 and the aqueous layer was washed 2× with MTB-ether. The aqueous layer was adjusted to pH ˜2 by addition of 6N hydrochloric acid and extracted 3× with MTB-ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 636 mg of the title compound of the formula