Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][C:3]=1[O:18][CH3:19].Br[CH2:21][C:22]([C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])=[O:23]>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]([C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])=[O:23]
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCC(=O)c1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione was reacted with 4-bromoacetyl-5-methyl-2-phenyloxazole to obtain 5-[3-[3-methoxy-4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]phenyl]propyl]-2,4-oxazolidinedione as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH:13]([N:16](CC)C(C)C)(C)[CH3:14].BrCC#N.O>O1CCCC1>[C:13]([CH2:14][NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: N#CCBr
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C)c(NCC#N)c1
Reaction time: 12 h

Procedure:
To a stirred solution of 3-amino-4-methyl-benzoic acid, methyl ester (10.0 g) in dry tetrahydrofuran was added N,N-diisopropylethylamine (12.6 mL) followed by the addition of bromoacetonitrile (5.1 mL). The reaction was heated at reflux under an atmosphere of nitrogen with stirring for 12 h. Water was added and the mixture extracted with ethyl acetate. The pooled organics were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the subtitle compound as a solid (12.4 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([NH2:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:21][N:13]([CH3:12])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(NC(=O)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A solution of 4-cyanobenzoyl chloride (2.5 g) in dichloromethane (50 ml) was added dropwise with stirring over 45 minutes to an ice-cold solution of t-butyl 2-methylcarbazate (2.0 g) in dichloromethane (50 ml) containing triethylamine (1.9 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then washed with water, dilute aqueous sodium bicarbonate solution and brine, dried (MgSO4) and evaporated. The residue was crystallised from ethyl acetate to give t-butyl 3-(4-cyanobenzoyl)-2-methylcarbazate (2.5 g) as a white solid; m.p. 179°-181° C.; NMR Spectrum (DMSO-d6) 1.27-1.55 (9H, br s), 3.10 (3H, br s), 8.00 (4H, s), 10.90 (1H, s); Mass Spectrum m/Z 276 (M+H)+ ; Elemental Analysis: calculated for C14H17N3O3 : C, 61.1%; H, 6.2%; N, 15.3%; found: C, 61.6%; H, 6.2%; N, 15.5%.
Reaction SMILES: [CH3:1][C:2]1C=CC(C(C)C)=C[CH:7]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[CH:2]([C:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][CH:18]=1)([CH3:7])[CH3:1]
Reactant: Cc1ccc(C(C)C)cc1
Reactant: c1ccc2ccccc2c1
Product: CC(C)c1cccc2ccccc12

Procedure:
Reaction was carried out similarly as in Example 11, but using p-cymene to transalkylate naphthalene. Yield of isopropylnaphthalene obtained was 21%, with 90% β- and 10% α-isopropylnaphthalene.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:21]([OH:23])=[O:22])[CH2:9][C:10]([C@@H:12]([NH2:20])[CH2:13][CH2:14][CH2:15][N:16]=[C:17]([NH2:19])[NH2:18])=[O:11])=[CH:3][CH:2]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(OCC)C>[C:25]([NH:20][CH:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[NH:18])[C:10](=[O:11])[CH2:9][CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:21]([OH:23])=[O:22])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(N)=NCCC[C@H](N)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N=C(N)NCCCC(NC(=O)c1ccccc1)C(=O)CC(Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
Arphamenine A hydrochloride (200 mg) was dissolved in 1 ml of water, and to the resulting solution were added 98 μl of benzoyl chloride and 119 mg of sodium carbonate, each in 1/5 portions at 30 minutes-interval and totally five times, under ice-cooling and stirring. After the reaction was completed, the reaction mixture was adjusted to pH 7.0 with 1N HCl, followed by addition of ethyl ether thereto. The precipitate as formed was washed with water and dried to give 225 mg of the titled compound as a colorless powder. This product gave a value of m/z 425 (MH+) in mass spectrometry.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c(OC)c1
Product: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)c(OC)c1
Yield: 73.6 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2,4-dimethoxyphenyl)benzamide (203.4 mg, 0.40 mmol) and acetic anhydride (0.046 ml, 0.49 mmol), the procedure of Inventive Example 94 was repeated to obtain 161.2 mg (73.6%) of the title compound in a colorless amorphous form.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]([F:24])[CH:16]=1>>[F:24][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][C:18]=1[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1F

Procedure:
Production Example 14 was repeated except that 4-(trifluoromethyl)phenylboronic acid and 4-bromo-2-fluorobenzenecarboxylic acid were used, to provide the title compound as white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=O)[CH:11](Cl)[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:15][C:16]([NH2:18])=[S:17].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:18][C:16]1[S:17][C:11]([CH3:12])=[C:10]([C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:15]=1
Reactant: CCOC(=O)C(=NOC)C(=O)C(C)Cl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOC)c1nc(N)sc1C
Temperature: 40 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
A mixture of ethyl 2-methoxyimino-2-(2-chloropropionyl)acetate (16.0 g.), thiourea (8.2 g.), sodium acetate (8.9 g.), water (50 ml.) and ethanol (50 ml.) was stirred at 40° C. for 3 hrs. Ethanol was distilled off in vacuo from the reaction mixture. Diisopropyl ether was added to the aqueous solution and stirred. The resultant precipitates were collected by filtration to give ethyl 2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 3.1 g.). The diisopropyl ether layer was separated from the filtrate, washed with water and an aqueous solution of sodium chloride successively, dried over magnesium sulfate and then filtered. The filtrate was evaporated in vacuo and the oily residue was treated with n-hexane. The precipitates were collected by filtration and washed with a small amount of diisopropyl ether to give the same product (0.9 g.) as above. Total yield 4.0 g.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.CN(OC)[C:14]([C:16]1[CH:20]=[CH:19][O:18][CH:17]=1)=[O:15]>CCOCC>[O:9]1[CH:10]=[CH:11][C:7]([C:14]([C:16]2[CH:20]=[CH:19][O:18][CH:17]=2)=[O:15])=[CH:8]1
Reactant: CON(C)C(=O)c1ccoc1
Reactant: Brc1ccoc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccoc1)c1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a solution of n-butyllithium (2.5M, 28 mL, 0.07 mol) in 150 mL of ether at -78° C. was added a solution of 3-bromofuran (10 g, 0.0628 mol) in 30 mL of ether over a 20 min period and the mixture was stirred at -78° C. for 20 min. To the above mixture was added 3-(N-methyl-N-methoxycarbamoyl)furan (9.16 g, 0.059 mol) in 30 mL of ether over a 15 min period and the mixture was stirred at room temperature for 1/2 h. The reaction mixture was quenched with 200 mL of ammonium chloride solution, 500 mL of methylene chloride was added and the mixture was stirred. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was triturated with 100 mL of hexane/TBME (9:1). The solid product was filtered and washed with TBME to afford 7.5 g (78.3%) of di-(3-furyl)ketone.
Reaction SMILES: C1COCC1.[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]2=[C:8]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=2)[CH:7]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>CCN(CC)CC>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:8]3[CH:7]=[N:6][N:10]4[CH:11]=[CH:12][CH:13]=[N:14][C:9]=34)[CH:20]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccnc(-c2cnn3cccnc23)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccnc(-c2cnn3cccnc23)c1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a THF suspension of 2-(pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-4-amine (8g) was added Et3N and 4-fluorobenzoyl chloride. The reaction mixture was stirred at 50° C. for 2 hours until LS/MS indicated the desired product was the major peak. After aqueous work up, the residue was dissolved in 1 ml of DMSO and purified by preparative HPLC. The product was obtained as a solid (10 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].C(N(CC)CC)C.[CH3:16][OH:17]>>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:17][CH3:16])=[O:5]
Reactant: CO
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCl
Temperature: 25 °C

Procedure:
219 g of chloropivaloyl chloride was added drop-by-drop to a chilled (0°-5° C.), stirred solution of 141.4 g of triethylamine in 320 g of anhydrous methanol. The resulting mixture was warmed to room temperature in one hour, and most of the methanol was evaporated under reduced pressure. The residue was drowned in water and extracted with ether. The extract was dried (MgSO4) and the solvent was evaporated. The residue was distilled to give methyl 3-chloro-2,2-dimethylpropionate (2A), b.p.: 40°-50° C. (14 Torr.).
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[NH:18][C:17](=[O:26])[C:16]=1[C:27]#[N:28]>C1(C)C=CC=CC=1>[CH3:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:26])[C:16]([C:27]#[N:28])=[C:15]2[N:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(Cl)c2c1
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Temperature: 110 °C
Yield: 92.1 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (8.73 g, 41.16 mmol) was added to a solution of Compound 106 (4.5 g, 20.08 mmol) in toluene (50 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0–2% methanol in dichloromethane gradient to yield 7.0 g (92%) of white solids. M.P. 269° C. 1H NMR (DMSO-d6): δ 2.34 (s, 3H), 3.65 (m, 4H), 3.92 (m, 4H), 7.14 (m, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.49 (d, J=3.5 Hz, 1H), 7.51 (s, 1H), 7.81 (d, J=4.8 Hz, 1H). EIMS m/z 379 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].Cl[C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Oc1ccc2c(nnn2CC2CCC2)c1Br
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cccnc1Oc1ccc2c(nnn2CC2CCC2)c1Br

Procedure:
A mixture of 4-bromo-1-(cyclobutylmethyl)-1H-benzotriazol-5-ol (3-5, 25 mg, 0.12 mmol, 1 equiv), 2-chloropyridine-3-carbonitrile (76 mg, 0.62 mmol, 5.0 equiv) and potassium carbonate (34 mg, 0.25 mmol, 5.0 equiv) in acetonitrile (3 mL) was irradiated at 170° C. in microwave reactor for 10 min. The mixture was purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to give 2-{[4-bromo-1-(cyclobutylmethyl)-1H-benzotriazol-5-yl]oxy}pyridine-3-carbonitrile (1) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.26 (dd, 1H, J=4.9, 1.8 Hz), 8.08 (dd, 1H, J=7.3, 1.8 Hz), 7.54 (d, 1H, J=8.8 Hz), 7.39 (d, 1H, J=8.8 Hz), 7.15 (dd, 1H, J=7.3, 4.9 Hz), 4.66 (d, 2H, J=7.3 Hz), 3.00 (p, 1H, J=7.3 Hz), 2.11 (m, 2H), 1.92 (m, 4H) ppm. LRMS m/z (M+H) 386.0 found, 386.0 required.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[CH2:21]([NH2:24])[CH2:22][CH3:23]>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:24][CH2:21][CH2:22][CH3:23])[N:3]=1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: CCCN
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCCNc1nc(Cl)nc2c1ncn2C(C)CC
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.132 ml 1-propanamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, followed by taking up in 5 ml of ethyl acetate, evaporating to dryness, impasting in 5 ml of pentane at ambient temperature, separating, washing with 5 ml of pentane and drying at a temperature of approximately 50° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Br[C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
Temperature: 60 °C

Procedure:
To a solution of {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (4.0 g, 11.2 mmol, 1.0 equiv) and 2,5-dibromopyridine (3.2 g, 13.4 mmol, 1.2 equiv) in 50 Ml toluene/ethanol (1:1) was added 2 M Na2CO3 (16.8 Ml, 3 equiv) followed by Pd(PPh3)4 (0.38 g, 0.34 mmol, 0.03 equiv). The biphasic mixture was sparged with nitrogen for 10 min, then heated to 60° C. for 3 days. The reaction was cooled to room temperature and then partitioned between ethyl acetate and saturated ammonium chloride solution. The organic extracts were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Purification by silica gel chromatography (7-40% EtOAc in hexanes) afforded the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.11 (dd, J=13.01, 2.15 Hz, 2H) 1.41-1.54 (m, 2H) 1.76-1.90 (m, 5H) 2.20 (d, J=6.57 Hz, 2H) 2.46 (tt, J=12.09, 3.19 Hz, 1H) 3.62 (s, 3H) 7.23 (d, J=8.08 Hz, 2H) 7.53 (dd, J=8.59, 0.76 Hz, 1H) 7.77 (dd, J=8.46, 2.40 Hz, 1H) 7.81 (q, J=3.87 Hz, 1H) 7.81 (d, J=8.34 Hz, 1H) 8.64 (d, J=1.77 Hz, 1H); (M+H)+390.0.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10]([Cl:18])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Into a 25 ml round bottom flask was weighed 5 grams (0.0237 mole) of 4-t-butylazo-4-cyanovaleric acid and then 15 ml of benzene and 2 ml of thionyl chloride were added. The acid dissolved and the solution was stirred for 4 hours at 25° C. ± 2° C. (protected from the atmosphere by a CaCl2 tube). At the end of the stirring period the benzene and excess thionyl chloride were evaporated under reduced pressure leaving 5.35 grams (98.8% yield) of 4-t-butylazo-4-cyanovaleryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=1[CH3:20].C(Cl)CCl>C(Cl)Cl>[NH2:12][C:13]1[CH:18]=[C:17]([NH:19][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][C:14]=1[CH3:20]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(N)cc1N
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3,4-dichlorobenzoic acid (200 mg, 1.05 mmol), 2,4-diaminotoluene (513 mg, 4.20 mmol), and EDC (403 mg, 2.10 mmol) was added CH2Cl2 (40 mL). The mixture was stirred overnight at RT, concentrated, diluted with EtOAc and extracted with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (n-Hexanes→50% EtOAc/n-Hexanes) yielding N-(3-amino-4-methyl-phenyl)-3,4-dichloro-benzamide. MS m/z=295, 297 [M]+ and [M+]+. Calc'd for C14H12Cl2N2O: 295.17.
Reaction SMILES: N1C=CN=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[N:14]([CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)[OH:19])=[N+:15]=[N-:16].O>CN(C)C=O>[N:14]([CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=1)[O:19][Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][CH3:7])=[N+:15]=[N-:16]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC[Si](CC)(CC)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.3 %

Procedure:
Imidazole (0.46 g) and triethylsilyl chloride (0.82 g) were added to a solution of N-[5-((R)-2-azido-1-hydroxyethyl)-2-benzyloxyphenyl]methanesulfonamide (1.64 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 12 hrs. Imidazole (0.15 g) and triethylsilyl chloride (0.21 g) were added to the reaction mixture. After being stirred for additional 3 hrs, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to afford the title compound (1.84 g).
Reaction SMILES: [ClH:1].[O:2]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][NH2:15])[CH3:3].[OH-].[K+].[C:18](OC(=O)C)(=O)[CH3:19]>>[ClH:1].[CH2:18]([NH:15][CH2:14][CH:9]1[C:10]2[C:5](=[C:4]([O:2][CH3:3])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1CCCC2CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCNCC1CCCc2c(OC)cccc21

Procedure:
The product from Example 14 was treated with KOH to give the free base, then reacted with acetic anhydride affording the amide. Anal. calcd. for C14H19NO2 : C, 72.07; H, 8.21; N, 6.00. Found: C, 72.03; H,.8.25; N, 6.01. This amide was reduced using the procedure of Example 5 to give the desired compound. Anal. calcd. for C14H22ClNO: C, 65.74; H, 8.67; N, 5.48. Found: C, 65.71; H, 8.61; N, 5.47.
Reaction SMILES: CN1CCCC1=O.[F:8][C:9]1[C:10]([NH:17][CH3:18])=[N:11][C:12](F)=[C:13]([F:15])[CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([NH:26][C:12]1[C:13]([F:15])=[CH:14][C:9]([F:8])=[C:10]([NH:17][CH3:18])[N:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNc1nc(F)c(F)cc1F
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CNc1nc(NCc2ccccc2)c(F)cc1F
Temperature: 140 °C
Reaction time: 19 h

Procedure:
To 20 ml of N-methylpyrrolidone were added all amount of the above-described 3,5,6-trifluoro-2-(methylamino)-pyridine together with 10 g of benzylamine, and the mixture was stirred at 140° C. for 19 hours and allowed to cool. To the solution was added 50 ml of chloroform and the mixture was washed six times with 200 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a crude oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11].Cl.[O-:21][C:22]#[N:23].[K+]>O.CO>[C:22]([NH:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11])(=[O:21])[NH2:23]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CNC(N)=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Of the compound from Example 40A, 192 mg (0.63 mmol) were introduced in 11 ml of water/methanol 1:2 and admixed in succession at RT with 0.63 ml (0.63 mmol) of 1M hydrochloric acid and 166 mg (2.05 mmol) of potassium cyanate. The reaction mixture was stirred at RT overnight and then freed from the methanol on a rotary evaporator. The residue was taken up in DMSO and purified by preparative HPLC [Method 20]. The product fraction was concentrated on a rotary evaporator. Drying of the residue in an HV gave 177 mg (73% of theory) of the title compound.