Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH:8]2[CH2:9][CH2:10][CH:4]1[CH2:5][N:6]([CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH2:7]2.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][CH2:13][CH2:12][CH2:11][N:6]2[CH2:7][CH:8]3[CH:3]([N:2]([CH3:1])[C:24](=[O:25])[O:26][CH2:27][CH3:28])[CH:4]([CH2:10][CH2:9]3)[CH2:5]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CNC1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
A mixture of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Preparation G; 74.6 mg, 0.25 mmol) and ethyl chloroformate (29.8 mg, 0.27 mmol) in DMF (2.5 mL) was stirred at rt for 24 h. Mass spectroscopic analysis showed that the amine starting material had not been totally consumed, and so additional ethyl chloroformate (50 μL) was added. The mixture was stirred overnight, after which time it was concentrated in vacuo. The resulting residue was dissolved in a mixture of DCM (0.5 mL) and MeCN (2 mL). K2CO3 (100 mg, 0.7 mmol) was added and the mixture stirred for 4 h. Filtration of the mixture and evaporation of the filtrate gave a residue that was dissolved in CHCl3 (1 mL). The solution was filtered through an ion-exchange solid-phase extraction plug (CBA, 2 g). The source flask was washed with additional CHCl3 (0.75 mL), which was then added to the extraction plug, and eluted as fraction 1. The plug was then eluted with CHCl3:MeOH:TEA (8:1:1; 4×2 mL) to give further fractions that were found not to contain any product. Fraction 1 was then added to a silica plug, which was eluted with CHCl3:MeCN (4:1; 3×2.5 mL). Evaporation of the fractions collected gave 79.6 mg (85.9%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[C:47]([C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)([CH3:50])([CH3:49])[CH3:48]>>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:38]=[C:2]([C:54]3[CH:55]=[CH:56][C:51]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:52][CH:53]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 86.5 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-tert-butyl phenyl boronic acid (0.125 mg, 0.69 mmol) by following general procedure D yielding the title compound (95 mg, 85%) as a white solid.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][O:13][C:14]1[C:19]2[CH:20]=[CH:21][S:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>O1CCCC1>[CH3:12][O:13][C:14]1[C:19]2[CH:20]=[C:21]([B:27]([OH:28])[OH:26])[S:22][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2sccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc2sc(B(O)O)cc12
Reaction time: 0.5 h
Yield: 62 %

Procedure:
2.5 M Hexane solution of normal butyl lithium (1.07 mL, 2.67 mmol) was slowly added under nitrogen to the 4-methoxybenzothiophene (92a, 368 mg, 2.24 mmol) obtained in Preparation Example 1 dissolved in an anhydrous tetrahydrofuran solution at −78° C., and the reaction mixture was stirred for 30 minutes. To the reaction mixture was slowly added a triisopropylborate solution (i-PrO)3B) (0.55 mL, 2.69 mmol) at room temperature, stirred for one hour, and the reaction was terminated by adding a solution of 2N hydrochloride. The resulting product was extracted with ethyl acetate, evaporated after a treatment with sodium sulfate, and concentrated under reduced pressure, recrystallized and filtered using hexane and ethyl acetate to give the target product 4-methoxybenzothiophene-2-boronic acid (95a, 289 mg, 62%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]2[Br:39])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH3:7])[CH:10]=1)[C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]2[Br:39])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(CBr)c1
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1Cc1cccc(OC)c1
Reaction time: 23 h
Yield: 84 %

Procedure:
Powdered potassium carbonate (2.79 g, 20.2 mmol) and 3-methoxybenzyl bromide (2.03 g, 10.1 mmol) were added successively to a stirred solution of ethyl 5-(benzyloxy)-3-bromo-1H-indole-2-carboxylate, Lit. WO96/18393 (3.63 g, 9.70 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred for 23 h and then diluted with water (250 mL). The product was extracted with ethyl acetate (3×100 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Recrystalization of the residue using methanol afforded 4.03 g (84%) of the desired product. The product had: 1H NMR (300 MHz, CDCl3) δ 7.05-7.91 (m, 9 H), 6.74 (dd, 1 H), 6.53-6.63 (m, 2 H), 5.37 (s, 2 H), 4.37 (q, 2 H), 3.71 (s, 3 H), 1.39 (t, 3 H); mass spectroscopy gave MH+=494.1 (calc'd exact mass for C26H24BrNO4=493.09).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](=O)[CH2:13]Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][NH:21][C:22]([NH2:24])=[S:23].N.O>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]3[N:24]=[C:22]([NH:21][CH3:20])[S:23][CH:13]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNC(N)=S
Reactant: O=C(CCl)c1ccc(OCc2ccc(Cl)cc2)cc1
Agent: N
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
A 1.43 g portion of 4-(4-chlorobenzyloxy)phenacyl chloride and 495 mg of 1-methylthiourea were stirred in 30 ml of ethanol at 70° C. for 30 minutes. After cooling, 10 ml of aqueous ammonia was added to stir at room temperature for 10 minutes. Water was added to extract with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off, thus yielding 1.47 g (89.1%) of 4-[4-(4-chlorobenzyloxy)phenyl]-2-methylaminothiazole. Recrystallization from ethyl acetate afforded crystals of m.p. 158°-159° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][C:24]1[O:25][CH:26]=[CH:27][N:28]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13]([NH:23][C:24]2[O:25][CH:26]=[CH:27][N:28]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1ncco1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ncco1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of 15.9 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 210 ml of ethyl acetate was added with stirring at 5°-8° C. under nitrogen to a solution of 3.57 g of 2-amino-oxazole and 4.3 g of triethylamine in 50 ml of ethyl acetate and after the temperature returned to room temperature, it stood overnight at that temperature. The mixture was vacuum filtered and the filtrate was washed and evaporated to dryness under reduced pressure. The 14.23 g of residue was triturated with 100 ml of N sodium hydroxide solution for 3 hours and was then diluted with 200 ml of water. The mixture was vacuum filtered and the filtrate was treated with activated carbon. The pH was adjusted to 1 by addition of N hydrochloric acid and the mixture was vacuum filtered. The recovered product was washed with water and dissolved in ethyl acetate. The solution was evaporated to dryness and the 8.77 g of product were crystallized twice from acetic acid to obtain 5.73 g (30.8% yield) of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(oxazol-2-yl)-3-quinoline-carboxamide melting at 258° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[C:10]2[CH:19]([C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[O:16][CH3:15])[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: COc1ccc2ccc(O)c(C(c3ccccc3OC)N3CCCCC3)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-methoxy-2-naphthol and 1-(2-methoxy-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 32.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=O)=[CH:11][CH:10]=1.S(Cl)(Cl)=O>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]2[O:18][CH2:17][CH2:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: O=C(NCCO)c1ccc(OCCCCCCBr)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: BrCCCCCCOc1ccc(C2=NCCO2)cc1
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To 100 g of 4-(6-bromohexyloxy)-N-(2-hydroxyethyl)benzamide was added dropwise 112 g (75 ml) of thionyl chloride over a 20 minute period. The mixture was stirred for 45 minutes and then diluted with several volumes of ether. A solid product separated which was collected and rinsed with ether to give 90 g of 2-[4-(6-bromohexyloxy)phenyl]-4,5-dihydro-oxazole.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:14]2[N:20]=[CH:19][N:18]=[C:17](Cl)[C:15]=2[N:16]=1>C1C=CC=CC=1.O1CCOCC1>[CH2:1]([O:8][C:17]1[C:15]2[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:22]3[CH2:23][CH2:24][S:25](=[O:28])[CH2:26][CH2:27]3)[C:14]=2[N:20]=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=S1CCN(c2nc(Cl)nc3c(OCc4ccccc4)ncnc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An alcoholate solution, prepared from 22 gm (0.2 mol) of benzyl alcohol in 100 ml of absolute benzene with 1.6 gm (0.07 mol) of sodium, was added to a solution of 15.9 gm (0.05 mol) of 2,8-dichloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]-pyrimidine in 400 ml of dioxane at about 30° C., and the mixture thus obtained was stirred at room temperature for about two hours. The reaction mixture was then evaporated in vacuo, and the residue was admixed with about 500 ml of water. The precipitate which solidified after standing for a short time, was filtered off, washed with water and dried at about 70° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([SH:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13]I>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:13])[N:7]=1
Reactant: CI
Reactant: CSc1nc(N)nc(S)c1C#N
Solvent: CC(C)=O
Product: CSc1nc(N)nc(SC)c1C#N
Temperature: 80 °C

Procedure:
To a 50 mL round-bottomed flask were added 2-Amino-4-mercapto-6-methylsulfanyl-pyrimidine-5-carbonitrile (3:50 mg, 2.5 mmol, 1.0 eq.), methyl iodide (8.2 mmol), and acetone (10 mL). The reaction mixture was heated at 80° C. for 5 min. The precipitate was filtered and gave to white solid. No further purification was necessary (312 mg, 58%). LC-MS: (ES+) m/z 213 (M+1). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 2.52 (s, 3H), 2.46 (s, 3H) ppm
Reaction SMILES: Cl.C([O:4][C:5](=[O:21])[CH:6]([CH2:16][S:17]C(=O)C)[CH:7]([C:9]1[CH:10]=[N:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH3:8])C>>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([CH:7]([CH3:8])[CH:6]([CH2:16][SH:17])[C:5]([OH:21])=[O:4])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(CSC(C)=O)C(C)c1ccc(N)nc1
Agent: Cl
Product: CC(c1ccc(N)nc1)C(CS)C(=O)O
Yield: 106.5 %

Procedure:
Conc. hydrochloric acid (4 mL) was added to 2-acetylsulfanylmethyl-3-(6amino-pyridin-3-yl)-butyric acid ethyl ester (104 mg, 0.253 mmol) under argon. The reaction was heated to reflux for 5 h and then concentrated under reduced pressure to give a diastereomeric mixture of the title compound (61 mg, 92%) as the hydrochloride salt.
Reaction SMILES: CC(C)(OC([NH:7][NH:8][C:9](=[O:27])[CH:10]=[CH:11][C:12]1[NH:13][CH:14]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:18])[CH:17]=1)=O)C>FC(F)(F)C(O)=O>[O:18]=[C:16]1[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][NH:13][C:12]([CH:11]=[CH:10][C:9]([NH:8][NH2:7])=[O:27])=[CH:17]1
Reactant: CC(C)(C)OC(=O)NNC(=O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Reaction time: 0.33 h

Procedure:
3-[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid, 2-[(1,1-dimethylethoxy)carbonyl]hydrazide (3.86 g) was stirred for one-half hour in 30 ml of trifluoroacetic acid at 0°-5° C. The trifluoroacetic acid salt of the title compound precipitated after adding 50 ml of diethylether. The salt was suspended in 30 ml of water, stirred with 2 g of sodium bicarbonate for 20 minutes, and the title compound was filtered off, washed with water and dried yielding a beige powder. Yield: 2.75 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Cl)[CH:6]=[CH:7][CH:8]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11].P>C1(C)C=CC=CC=1.C(Cl)C=CC1C=CC=CC=1.[Pd]>[O:2]([C:3]1[CH:4]=[C:5]([CH2:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1)[CH3:1]
Reactant: COc1cccc(Cl)c1
Reactant: CC(=O)c1ccccc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: Cc1ccccc1
Product: COc1cccc(CC(=O)c2ccccc2)c1
Yield: 83.5 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are m-methoxyphenyl chloride (142.7 mg, 1.0 mmol), acetophenone (299.9 mg, 2.5 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (18.3 mg, 0.045 mmol), K3PO43H2O (663.9 mg, 2.5 mmol) in 3 mL dry toluene at 110° C. for 12 h. 2-(3′-Methoxylphenyl)-1-phenyl-1-ethanone (189.0 mg) was obtained with a yield of 84% as liquids. 1H NMR (300 MHz, CDCl3) δ 8.02-7.96 (m, 2H, ArH), 7.55-7.47 (m, 1H, ArH), 7.46-7.38 (m, 2H, ArH), 7.21 (t, J=7.8 Hz, 1H, ArH), 6.87-6.73 (m, 3H, ArH), 4.22 (s, 2H, CH2), 3.73 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 197.3, 159.6, 136.3, 135.9, 133.0, 129.5, 128.47, 128.45, 121.6, 115.0, 112.2, 55.0, 45.4; IR (neat) v (cm−1) 3058, 3002, 2938, 2835, 1682, 1597, 1490, 1448, 1317, 1263, 1211, 1153, 1050, 1020, 1001; MS (70 eV, EI) m/z (%): 227 (M++1, 2.28), 226 (M+, 12.78), 105 (100).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Product: Cc1c(Cl)ccc(C(=O)Cl)c1Cl
Temperature: 25 °C

Procedure:
A 500 ml. three-necked flat-bottomed flask equipped with a reflux condenser, a thermometer and a Teflon agitator inside was charged with 205 g (1.0 mole) of 2,4-dichloro-3-methylbenzoic acid and 300 g (2.5 moles) of thionyl chloride. With stirring, they were reacted at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and the excess of thionyl chloride was distilled off by a rotary evaporator. The residue was dried under reduced pressure to give crude 2,4-dichloro-3-methylbenzoyl chloride as yellow crystals containing a small amount of a yellowish brown liquid. This product was distilled under reduced pressure to recover a fraction having a boiling point of 125° to 128° C. at 6 mmHg which was the desired product having a high purity. The amount of 2,4-dichloro-3-methylbenzoyl chloride obtained was 176.2 g (yield 79 mole%). The product had a melting point of 43.2° to 47.2° C. The structure of the 2,4-dichloro-3-methylbenzoyl chloride was determined by infrared absorption spectroscopy, mass spectroscopy, NMR spectroscopy and elemental analysis.
Reaction SMILES: [CH:1]1([CH2:4][C:5](Cl)=O)[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[C:13]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:21][CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:21]2[C:10]3[CH:11]=[CH:12][C:13]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:14][C:9]=3[N:8]=[C:5]2[CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:24][CH2:25]1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Reactant: O=C(Cl)CC1CC1
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC1CC1)n2CC1CC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 5 from cyclopropylacetyl chloride (Step A) and 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E of Example 1).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1>CO.[Pd]>[OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
To a solution of methyl (6-hydroxy-1-benzofuran-3-yl)acetate (11.4 g, 55.3 mmol) in methanol (100 mL) was added 10% palladium on carbon (50% water wet, 2 g), and the mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 18 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (8.74 g, yield 76%) as colorless prism crystals.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CCOCC>[OH:19][C:13]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc2cc(Br)sc2c1
Reactant: O=C1CCCCC1
Solvent: O
Solvent: CCOCC
Product: COc1ccc2cc(C3(O)CCCCC3)sc2c1
Yield: 41.7 %

Procedure:
To Mg (0.22 g, 9.05 mmol) under argon in Et2O (20 ml) was added dropwise a solution of bromide (4) (2.00 g, 8.23 mmol) in Et2O (20 ml). The mixture was refluxed for 2 h, a solution of cyclohexanone (1.00 ml, 9.87 mmol) in Et2O (5 ml) was added and the mixture was refluxed for 2 h. It was poured into iced water. The solution was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give 8.00 g as an oil. Triturating from diisopropyl ether afforded 2-(1-hydroxycyclohexyl)-6-methoxybenzothiophene as a white powder (0.90 g, 65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[N:11]1([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=3)[N:22]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:14]1[CH2:13][CH2:12][N:11]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:27])([F:28])[F:29])=[N:24][N:25]=3)[N:22]=2)[CH2:16][CH2:15]1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: O=S(=O)(c1ccccn1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 32 %

Procedure:
Obtained in 32% yield by an analogous method to Example 394, starting from pyridine-2-sulfonyl chloride and 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:23])[CH3:22]
Reactant: NCCC=C1c2ccccc2C=Cc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
5-(3-Aminopropylidene)-5-H-dibenzo[a,d]cycloheptene is dissolved in acetic anhydride and the solution is heated to refluxing for 20 minutes. The solution is then cooled and poured into a large volume of water. The mixture is stirred until the excess acetic anhydride is hydrolyzed. The product is extracted into ether, the extract washed with sodium bicarbonate solution, followed by washing with water and dried over sodium sulfate. The product is isolated by evaporating the ether.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Oc2ccccc2)cc1C(F)(F)F
Reaction time: 72 h

Procedure:
To a solution of methyl 4-(phenyloxy)-2-(trifluoromethyl)benzoate (for a preparation see Intermediate 34) (0.516 g, 1.74 mmol) in ethanol (17.5 ml), was added a 2 M aqueous sodium hydroxide (1.5 ml). The solution was stirred and left to stand over 3 days. The solvent was removed in vacuo and then water added. The solution was made acidic with dilute aqueous HCl and the resulting white precipitate extracted into chloroform. The phases were separated using a hydrophobic frit. The solvent was removed in vacuo to give the title compound as a white solid (0.508 g); LCMS: (System 4) (M-H)−=281, tRET=2.85 min.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10](O)([CH3:19])[O:9][N:8]=2)=[CH:4][CH:3]=1.[K+].[Br-]>>[Cl:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([CH3:19])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(O)ON=C(c2ccc(Cl)o2)C1c1ccc(F)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1onc(-c2ccc(Cl)o2)c1-c1ccc(F)cc1
Yield: 89 %

Procedure:
Prepared by dehydration/aromatisation of 3-(5-chlorofuran-2-yl)-4-(4-fluorophenyl)-5-hydroxy-5-methyl-2-isoxazoline. 89% yield. M.p. 103.7-105.2° C. FT-IR (KBr): 3147, 3077, 2931, 1637, 1595, 1522, 1508, 1445, 1418, 1403, 1236, 1230, 1223, 1203, 1158, 1135, 1018, 987, 939, 921, 896, 846, 794 cm−1. 1H NMR (500 MHz, CDCl3, δ): 7.28-7.26 (m, 2H, aromatic protons); 7.16-7.13 (m, 2H, aromatic protons); 6.29 (d, J=3.5 Hz, 1H, furyl proton); 6.15 (d, J=3.5 Hz, 1H, furyl proton); 2.37 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3, δ): 167.0, 163.6, 161.7, 152.2, 143.4, 138.5, 131.8, 131.7, 125.3, 125.3, 116.0, 115.8, 113.8, 113.5, 107.9, 11.2. GC-MS (70 eV) m/z (rel.int.): 279 (M++2, 16), 277 (M+, 49), 237 (35), 236 (19), 235 (100), 234 (12), 206 (12), 172 (46), 171 (20), 170 (11), 147 (16), 145 (20), 89 (13), 43 (30). Anal. Calc. for C14H9ClFNO2: C, 60.56; H, 3.27; N, 5.04. Found: C, 60.58; H, 3.24; N, 5.01.