Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([OH:40])[CH2:20][CH:19]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH:17]2[CH:13]1[CH2:14][N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:16]2>CS(C)=O.O>[C:1]([CH2:21][CH:19]1[CH2:18][CH:17]2[CH:13]([CH2:14][N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:16]2)[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH3:4])([OH:40])[CH2:20]1)#[N:2]
Reactant: COc1ccccc1C1(O)CC(COS(=O)(=O)c2ccc(C)cc2)CC2CN(C(=O)OC(C)(C)C)CC21
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C1(O)CC(CC#N)CC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 50 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
40 g of potassium cyanide are added carefully to a solution of 215 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-tert-butyloxycarbonyl-6-tosyloxymethylperhydroisoindol-4-ol in 800 cm3 of dimethyl sulphoxide. The reaction mixture is stirred at 50° C. for 20 hours, diluted with 1 liter of water and extracted with twice 200 cm3 and then 100 cm3 of ethyl acetate. The combined organic extracts are washed with twice 500 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is recrystallized from 200 cm3 of ethyl ether, and the crystals are washed with the same solvent, drained and then dried under reduced pressure (2.7 kPa). 142 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-(2-methoxyphenyl)-2-tert-butyloxycarbonylperhydroisoindol-4-ol are obtained in the form of a white solid. M.p.K =149° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:37][CH2:38][C:39]2[CH:47]=[CH:46][C:42]([C:43](O)=O)=[CH:41][CH:40]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:37][CH2:38][C:39]2[CH:47]=[CH:46][C:42]([CH2:43][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:41][CH:40]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(CCN2CCCCCC2)cc1
Reactant: CCNc1ccc(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: COc1ccc(NCCCc2ccc(CCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)c1
Yield: 59.5 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(2-azepan-1-ylethyl)benzoic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 152, the title compound (40 mg) was obtained.
Reaction SMILES: [C:1]([C:3]([C:16](=[O:32])[N:17]([CH2:28][CH:29]1CC1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[CH:4][NH:5][C:6](=[NH:15])[N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]1=[O:14])#[N:2].C(O)(=O)[C:34](O)=[O:35]>C(O)(=O)C>[CH3:34][O:35][CH2:29][CH2:28][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=1)[C:16]([C:3]1[C:1]([NH2:2])=[N:15][C:6]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[NH:9][C:8]2=[O:14])=[N:5][CH:4]=1)=[O:32]
Reactant: CC1(C)CN(C(=N)NC=C(C#N)C(=O)N(CC2CC2)c2cccc(C(F)(F)F)c2)C(=O)N1
Reactant: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: COCCN(C(=O)c1cnc(N2CC(C)(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Yield: 146.5 %

Procedure:
As in Example 118 and starting from 4.52 g (10 mmol) of a compound II (R1, R2 =CH3 ; R3, R5, R6 =H; R4 =CH3OCH2CH2), 360 mg of anhydrous oxalic acid and 7 ml of glacial acetic acid, 2.65 g (=58.6% yield) of pure 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)-pyrimidine-5-carboxylic acid N-(2-methoxyethyl)-N-(3-trifluoromethylphenyl)amide were obtained, melting point 192°-93°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2C=C[CH:45]=[CH:44][CH:43]=2)=[O:32])[CH:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]([NH:14]C(=O)C(Cl)(Cl)Cl)=[O:13].[OH-].[Na+]>C(Cl)Cl.CO>[CH2:34]([NH:33][C:31]([C:4]1[CH:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[C:7]([O:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])=[C:2]([Br:1])[CH:3]=1)=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: O=C(NCCOc1c(Br)cc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1cccc(C(F)(F)F)c1)NC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCNC(N)=O)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 5-bromo-N-(8-phenyloctyl)-6-[2-({[(2,2,2-trichloroacetyl) amino]carbonyl} amino)ethoxy]-3′-(trifluoromethyl)[1,1′-biphenyl]-3-carboxamide in CH2Cl2/MeOH (10/4) (14 mL) was added 1M NaOH (2 mL). The reaction was stirred at rt overnight and concentrated in vacuo. The residue was extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (3 to 5% MeOH:CH2Cl2) to afford the title compound (0.203 g, 92%) as a white solid. mp 122.5-125.1° C. 1H NMR (DMSO-d6) δ 8.58 (bt, 1H); 8.12 (d, 1H); 7.90 (m, 3H); 7.78 (d, 1H); 7.73 (dd, 1H); 6.95 (t, 1H); 5.44 (s, 2H); 3.48 (dd, 2H); 3.24 (dd, 2H); 3.05 (ddd, 2H); 1.48 (dd, 2H); 1.25 (m, 18H); 0.84 (t, 3H); IR (KBr) 3300, 2950, 2820, 1650, 1600, 1550, 1460, 1330, 1180, 1120, 1080, 1030, 900, 805 cm−1; mass spectrum [(+)ESI], m/z 614/616 (M+H)+; Anal. Calcd. for C29H39BrF3N3O3: C, 56.68; H, 6.40; N, 6.84, Found: C, 56.37; H, 6.25; N, 6.49.
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:21]([CH3:23])[CH3:22])[CH:3]=1.[N:24]([C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1)=[C:25]=S>C(Cl)CCl>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([N:21]([CH3:23])[CH3:22])=[CH:3][C:2]4[NH:1][C:25]([NH:24][C:27]5[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=5)=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: CN(C)c1cc(N)c(N)cc1C(=O)Nc1ccc2cn[nH]c2c1
Reactant: Cc1cccnc1N=C=S
Solvent: ClCCCl
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4cn[nH]c4c3)c(N(C)C)cc2[nH]1

Procedure:
4,5-diamino-2-dimethylamino-N-(1H-indazol-6-yl)benzamide (see Example 160; 0.3 mmol) was reacted with 2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from 2-amino-3-methylpyridine and thiophosgene employing procedure described in Example 115) followed by cyclization in situ using EDC as described in general procedure B to provide 6-dimethylamino-2-(3-methylpyridin-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide. MS: m/z 427 (M+H)+.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)C>[C:6]1([C:4]2[C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:19][CH2:16][CH2:17][N:18]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NCCN
Reactant: O=C(c1ccccc1)c1ccccc1F
Solvent: CCO
Product: c1ccc(C2=NCCNc3ccccc32)cc1
Temperature: 180 °C

Procedure:
A 5 mL microwave tube was charged with 2-fluorobenzophenone (0.40 g), ethylene diamine (0.40 g) and ethanol (4 mL). The mixture was heated in a microwave at 180° C. for 10 minutes. The contents were concentrated to an oil and dissolved in methylene chloride. The resulting solution was purified by silica gel chromatography. Any unreacted benzophenone was eluted with methylene chloride and then the desired product was eluted with 70% ethyl acetate in hexanes. Desired fractions were concentrated to provide 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine as a yellow crystalline solid. H1 NMR (d6-dmso): 7.30-7.42 (m, 5H), 7.12 (dd, 1H), 6.78 (d, 1H), 6.75 (d, 1H), 6.49 (dd, 1H), 6.05 (br t, 1H), 3.84 (m, 2H), 3.56 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]I.[H-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:17])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN=Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(N=Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 72 h
Yield: 92.7 %

Procedure:
To a solution of N'-benzylidenehydrazinecarboxylic acid tert-butylester (2.0 g, 9.07 mmol) in anhydrous tetrahydrofuran (20 ml) was added methyl iodide (4.54 ml, 72.6 mmol) and the solution was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.09 g, 27.2 mmol) was slowly added and the mixture was stirred at room temperature for 3 days. The tetrahydrofuran (50 ml) was added and the mixture was filtered. The filtrate was concentrated in vacuo and chromatographed on silica (100 g) with heptan:ethyl acetate (1:1) to give 1.97 g (93%) of N'-benzylidene-N-methylhydrazinecarboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: Cl.O1C=C[CH2:4][C:3]1=O.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11]>>[C:10]([CH:9]1[CH2:16][CH:15]([CH2:3][CH3:4])[O:14][C:8]1=[O:13])(=[O:11])[CH3:12]
Reactant: O=C1CC=CO1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Product: CCC1CC(C(C)=O)C(=O)O1
Reaction time: 8 h

Procedure:
The mixture was allowed to stand overnight and was transferred to a separatory funnel and acidified with 125 ml concentrated hydrochloric acid. The organic layer was separated and the water layer extracted three times with 50 ml diethyl ether. The extracts were combined with the organic layer, dried through sodium sulfate, and the diethyl ether was removed by means of a Rotovap. 182 Grams of product were obtained which when analyzed by GC indicated 83.6% lactone and 7.8% ethyl acetoacetate.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[NH2:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:17])[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Reactant: NCC1(Nc2ccccc2)CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.8 %

Procedure:
580 mg (1.94 mmol) of 2-bromo-N-(2,6-diisopropylphenyl)acetamide are added to 400 mg (1.96 mmol) of (1-aminomethylcyclohexyl)phenylamine (obtained in Example 2/b) in 20 ml of dimethylformamide. The reaction medium is stirred at room temperature for 48 h. It is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 60/40, v/v). 309 mg of N-(2,6-diisopropylphenyl)-2-[(1-phenylamino-cyclohexylmethyl)amino]acetamide are obtained in the form of a yellowish oil. Yield=37%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:25])([F:26])[F:27])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Reactant: OB(O)c1ccccn1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccccn4)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 2-pyridylboronic acid by the method described for Example 36 Step 3. MS (ES+) 521 ([MH]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[OH-].[K+].[CH3:11]O>CS(C)=O>[CH3:11][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1
Reactant: Cc1ccc(O)cn1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(C)nc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
150 ml of 3-hydroxy-6-methylpyridine are metered into a solution of 84 g of potassium hydroxide in 400 ml of methanol and 500 ml of dimethyl sulphoxide in the course of one hour. After removal of the methanol on a rotary evaporator, 213 g of methyl iodide, dissolved in 100 ml of dimethyl sulphoxide, are added dropwise, while cooling with ice, and the reaction mixture is stirred at 20° C. for 15 hours and subjected to steam distillation. The distillate is extracted continuously in the extractor with methylene chloride and the extract is concentrated. 85 g (56% of theory) of 5-methoxy-2-methylpyridine are obtained as a colourless oil.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[CH2:10]O.[NH:12]1C2=NC=CC=C2C(CN)=C1>>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[CH2:10][NH2:12]
Reactant: OCc1nc2cnccc2s1
Reactant: NCc1c[nH]c2ncccc12
Product: NCc1nc2cnccc2s1

Procedure:
Intermediate R was prepared from thiazolo[4,5-c]pyridin-2-ylmethanol (R-4) following similar procedures for synthesizing intermediate A from A-3, as described above. MS (m/z): 165 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[CH:7]=[C:6]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.O=P(Cl)(Cl)[Cl:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:25])[CH:7]=[C:6]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1
Reactant: COc1ccc2nc(O)cc(Nc3ccc(Cl)c(Cl)c3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(Cl)cc(Nc3ccc(Cl)c(Cl)c3)c2c1
Yield: 61 %

Procedure:
Prepared using general procedure 3; 6-Methoxy-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (1.05 g, 3.13 mmol) and 26 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 0.685 g of material (1.94 mmol, 61%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])/[C:3](/OS(C(F)(F)F)(=O)=O)=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)#[N:29]>O1CCOCC1>[C:28]([C:30]1[CH:35]=[C:34](/[C:3](/[C:2]([F:19])([F:18])[F:1])=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:33]=[CH:32][CH:31]=1)#[N:29]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)/C=C(\OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C(\c1cccc(C#N)c1)C(F)(F)F
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of ethyl (Z)-4,4,4-trifluoro-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-butenoate (250 mg, 0.79 mmol) in 5 ml anhydrous dioxane was added potassium phosphate (251 mg, 1.19 mmol), 3-cyanophenyl boronic acid (116 mg, 0.79 mmol), and tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 20% EtOAc in hexane as the eluent to give ethyl (2E)-3-(3-cyanophenyl)-4,4,4-trifluorobut-2-enoate (150 mg, 79%) as a yellow residue after drying. H1NMR (CDCl3) 1.107-1.142 (t, 3H); 4.04-4.107 (m, 2H); 6.684 (s, H); 7.38-7.72 (m, 4H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13].[Cl-].[NH4+].Cl>C(OCC)C>[OH:14][CH:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10][CH2:11][C:12]#[CH:13]
Reactant: C#CCCCO
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCCC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To an ice-cold solution of 3.0M phenylmagnesium bromide (100 mL, 300 mmol) under argon atmosphere was added dropwise pent-4-yn-1-ol (10 g, 120 mmol) in diethyl ether (20 mL). After stirring for 3 hours the solution was slowly added to an ice-cold solution of dilute ammonium chloride. 6N Hydrochloric acid was added to break up the gel and the layers were separated. The aqueous extract was washed with diethyl ether (3×50 mL) and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed by rotary evaporation under reduced pressure to give 17 g of the crude product which was Kugelrohr distilled to afford 11.1 g (58%) of the purified product. 1H NMR (CDCl3) δ: 1.82-1.95 (m, 2H), 1.98 (t, 1H), 2.20-2.35 (m, 2H), 2.40 (s, 1H), 4.80-4.85 (m, 1H), 7.30-7.38 (m, 5H) ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:29](N1C=C[N+](C)=C1)=[O:30]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:29]([N:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20]3)=[O:30])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C[n+]1ccn(C(=O)N2Cc3ccccc3C2)c1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(1,3-dihydro-isoindole-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (≈100). HPLC-MS m/z=401.1 (M+1), Rt: 5.1 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)[C:2]=1[Cl:1])[C:26]#[N:27]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
(+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (112 mg, 0.221 mmol) was taken up in DCM (3 mL) and TFA (0.341 mL, 4.43 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material was azeotroped 2× with DCM and 2× with MeOH, and then dried under vacuum. The solid was dissolved in EtOAc, and then washed with 2M K3PO4 solution. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-5% MeOH/DCM). (+/−) 3-amino-4-chloro-5-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (36 mg) was obtained as a colorless foam.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]1[C:12](=S)[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1.Cl.[NH2:19][OH:20].C(N(CC)CC)C>C(O)C>[OH:20][N:19]=[C:12]1[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8][C:7]1=[CH:6][C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1
Reactant: S=C1Nc2ccccc2SC1=Cc1ccc[nH]1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=C1Nc2ccccc2SC1=Cc1ccc[nH]1

Procedure:
A mixture of 2-[(pyrrol-2-yl)methylene]-2H-1,4-benzothiazine-3(4H)-thione (1.70 g, 6.6 mmol) (Example 270), hydroxylamine hydrochloride (1.38 g, 20.0 mmol) and triethylamine (2.18 g, 20.0 mmol) in dry ethanol (50 ml) was refluxed for 24 h with stirring. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using (9:1) hexane:ethanol as the mobile phase.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([O:17][CH3:16])=[C:19]([N:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)[CH:20]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)Cc1ccc(Br)c2ccccc12
Product: COc1ccc(NC(=O)Cc2ccc(Br)c3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 4-bromonaphth-1-ylacetic acid (J. Org. Chem., 1951, 16, 1588) and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) following a similar procedure to Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:16]([O:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[C:21]=1B1OC(C)(C)C(C)(C)O1)[CH2:17][CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:21]3[C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[CH:28][C:20]=3[O:19][CH2:16][CH2:17][CH3:18])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CCCOc1ccc2c(c1B1OC(C)(C)C(C)(C)O1)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)OCC)c[nH]c13)OCO2

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-propoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A32) the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.Br[CH2:24][CH2:25][O:26][CH3:27]>>[CH3:27][O:26][CH2:25][CH2:24][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22]
Reactant: COCCBr
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Product: COCCn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, colorless resin, MS: m/e=348.3 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and 2-bromoethyl-methylether.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:27]4[CH2:28][CH2:29][CH2:30][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Reactant: CN1CCCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CN1CCCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (4.1, 100 mg, 0.22 mmol), N-methylhomopiperazine (140 μL, 1.1 mmol), CuI (42 mg, 0.22 mmol), ethylene glycol (25 μL, 0.44 mmol), potassium phosphate (93 mg, 0.44 mmol) in 2 mL isopropanol in a sealed tube was stirred for 16 hrs at 120° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C20H23ClN6OS (M+H)+ 431.1, 433.1 (Cl pattern).