Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=2[F:21])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[F:25][C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=1.CCN(CC)CC.CCOC(C)=O>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([O:20][C:29]3[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=3)[C:14]=2[F:21])[O:11][CH3:12])=[CH:23][CH:24]=1)#[N:2]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(Oc2ccc(F)cc2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.8 %

Procedure:
To a solution of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-methoxy-acetamide (370 mg) in 1,2-dichloroethane (10 ml) was added copper(II)acetate (222 mg), 4-fluorobenzoic acid (467 mg) and powdered MS4 Å (2 g). Et3N (563 mg) was added and the mixture was stirred 2 days at rt. The mixture was passed over silica gel eluting with AcOEt. CC (AcOEt/Hept 1:3 to 3:1) yielded 203 mg (61%) of (RS)-N-(4-cyano-benzyl)-2-[2,6-difluoro-3-(4-fluoro-phenoxy)-phenyl]-2-methoxy-acetamide. Yellow oil. MS 427.0 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=3[OH:23])[CH2:10][CH2:9]2)[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(OC([N:38]1[CH2:41][CH:40](I)[CH2:39]1)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[NH:38]1[CH2:41][CH:40]([O:23][C:16]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:15]=2[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:9][CH2:10]2)[CH2:39]1
Reactant: Nc1ncnc(N2CCN(Cc3cc(Cl)c(Cl)cc3O)CC2)c1-c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc(N2CCN(Cc3cc(Cl)c(Cl)cc3OC3CNC3)CC2)c1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A reaction mixture of 2-{4-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-ylmethyl}-4,5-dichloro-phenol (80.0 mg; 0.18 mmol; 1.00 eq.), 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (60.6 mg; 0.21 mmol; 1.20 eq.) and cesium carbonate (116.2 mg; 0.36 mmol; 2.00 eq.) in DMF (1 ml) was stirred at 90° C. overnight. The reaction solution was poured to water and extracted with ethyl acetate, The separated organic layer was washed with brine, dried and concentrated, which was then dissolved in methanol (1 ml) followed by adding 4.0 M HCl in dioxane (2 ml) and stirred at RT overnight. The reaction mixture was concentrated and purified by Waters prep-HPLC (acidic condition) to yield the title compounds (37 mg, yield 33.6%). LC-MS: (M+1=504, obsd.=504/506).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=O.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].CO.[H-].[Na+]>CN(C=O)C>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:3][C:4]=1[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 95 °C

Procedure:
A solution of 3-dimethylamino-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)prop-2-en-1-one (14.4 mmol assumed) from Step A, cyanoacetamide (1.33 g, 15.8 mmol), and methanol (1.3 mL, 32 mmol) in DMF (35 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil) (1.45 g, 36 mmol) in DMF (16 mL) at rt. After the slow addition was complete, the reaction was heated to 95° C. for 2.5 h. Most of the DMF was then removed in vacuo before the reaction was diluted with aqueous 18% citric acid solution. The mixture was extracted twice with methylene chloride and the organic layers were washed with a portion of brine. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The solid residue was triturated with ether, filtered, and air dried to afford the product. HPLC/MS: 375 (M+1), 377 (M+3); Rt=3.47 min; 1H NMR (CDCl3): δ 6.96 (br d, J=8.4 Hz,2H), 7.14 (d, J=8.2 Hz, 1H), 7.25 (br d, J=8.4 Hz, 2H), 7.31 (dd, J=1.9 and 8.2 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.996 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([O:65][C:66]([C@@H:68]1[CH2:72][CH2:71][CH2:70][NH:69]1)=[O:67])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][C@H:68]1[C:66]([O:65][CH2:63][CH3:64])=[O:67])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-(ethoxycarbonyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [CH:1]([C:4]1[O:5][C:6]([CH3:15])=[CH:7][C:8](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:9]=1)([CH3:3])[CH3:2].[C:16]1([C:22]2[CH2:26][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[C:16]1([C:22]2[CH2:26][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]([C:33]3[CH:34]=[CH:35][C:36]([CH:37]=[CH:15][C:6]4[O:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8](=[C:10]([C:11]#[N:12])[C:13]#[N:14])[CH:7]=4)=[CH:39][CH:40]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(N2N=C(c3ccccc3)CC2c2ccccc2)cc1
Reactant: CC1=CC(=C(C#N)C#N)C=C(C(C)C)O1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)C1=CC(=C(C#N)C#N)C=C(C=Cc2ccc(N3N=C(c4ccccc4)CC3c3ccccc3)cc2)O1
Temperature: 75 °C

Procedure:
As shown in the following reaction 9, 0.5 g (2.5 mmol) of 2-(2-isopropyl-6-methyl-pyran-4-ylidene)-malononitrile and 0.815 g (2.5 mmol) of 4-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-benzaldehyde were added into 20 ml of ethanol, and 0.32 g (3.75 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[F:29][C:26]([F:27])([F:28])[C:24]1[N:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[N:16][CH:17]=2)[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[CH:23]=1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(-c2ccc(O)cc2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
In methanol (8 mL) and tetrahydrofuran (6 mL) was dissolved 2-[4-(benzyloxy)-phenyl]-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (0.77 g), and after adding palladium carbon (0.154 g) under nitrogen atmosphere, the atmosphere was replaced by hydrogen, and the mixture was stirred at room temperature for 5 hours. Insoluble material was filtered off by using a membrane filter, and the filtrate was concentrated under reduced pressure. The concentrate was diluted with methanol, activated charcoal was added thereto, and the mixture was filtered by using Celite. The filtrate was concentrated under reduced pressure and crystallized to obtain 4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol (0.612 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:15](=[O:16])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17].ClCCl.S(=O)(=O)(O)O.[CH2:26]=[C:27]([CH3:29])[CH3:28]>O1CCOCC1.O>[Cl:1][CH2:2][CH2:3][N:4]1[C:15](=[O:16])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([O:14][C:27]([CH3:29])([CH3:28])[CH3:26])=[O:13])[N:6]2[C:5]1=[O:17]
Reactant: C=C(C)C
Reactant: O=C(O)C1C=CCn2c(=O)n(CCCl)c(=O)n21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1C=CCn2c(=O)n(CCCl)c(=O)n21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
0.1 mol of 2-(2-chloroethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid was dissolved in 500 ml of dioxan or dichloromethane. 12 ml of concentrated sulphuric acid were added and the mixture was then treated with 500 ml of isobutene. After stirring at room temperature for 4 days, the mixture was diluted with water and extracted with ether. The ether extracts were washed with 10% sodium carbonate solution, dried over magnesium sulphate and evaporated to give tert.butyl 2-(2-chloroethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 87°-88° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[NH:24]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]1>CN(C=O)C>[ClH:1].[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][S:11]([C:9]2[S:10][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([O:29][CH:26]4[CH2:27][CH2:28][NH:24][CH2:25]4)[C:7]=3[CH:8]=2)(=[O:13])=[O:12])=[CH:16][CH:17]=1
Reactant: OC1CCNC1
Reactant: Cc1ccc(NS(=O)(=O)c2cc3c(Cl)nccc3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)c2cc3c(OC4CCNC4)nccc3s2)cc1
Product: Cl
Temperature: 200 °C

Procedure:
4-Chloro-N-(4-methylphenyl)thieno[3,2-c]pyridine-2-sulfonamide (60.0 mg, 0.17 mmol) in dry DMF (1 mL) and NaH (5.1 mg, 0.21 mmol) was added to pyrrolidin-3-ol (18.5 mg, 0.21 mmol) under nitrogen. The mixture was heated in the microwave at 200° C. in 5 min. The product was purified by preparative HPLC. Yield: 29.9 mg (43.4%). 1H NMR (270 MHz, CH3OH-d4) δ ppm 8.09 (s, 1H) 7.71 (d, J=6.93 Hz, 1H) 7.46 (d, J=6.93 Hz, 1H) 7.47-7.44 (m, 4H) 4.67 (d, J=3.22 Hz, 1H) 3.97 (s, 2H) 2.26 (s, 3H). LC-MS 390 (M−H)+; Purity (HPLC) 99%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(O[C:14](=[O:16])[CH3:15])(=O)C.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([NH:36][C:37]4[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][N:38]=4)[N:30]=3)=[CH:25][CH:24]=2)[CH2:19]1>C1COCC1>[CH3:35][C:33]1[CH:32]=[C:31]([NH:36][C:37]2[CH:42]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:40]=[CH:39][N:38]=2)[N:30]=[C:29]([C:26]2[CH:27]=[N:28][C:23]([N:20]3[CH2:21][CH2:22][C@H:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19]3)=[CH:24][CH:25]=2)[CH:34]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(N3CC[C@H](N)C3)nc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CCN(c2ccc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Diisopropylethylamine (0.032 mL, 0.181 mmol), acetic anhydride (6.26 μL, 0.066 mmol), 6′-[(3S)-3-aminopyrrolidin-1-yl]-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridin-6-amine (Example 5, 25 mg, 0.060 mmol), and THF (1 mL) were added to a flask and stirred at room temperature for 16 hours. The crude solution was purified via reverse phase high pressure liquid chromatography to afford N-[(3S)-1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)pyrrolidin-3-yl]acetamide. MS ESI calcd. for C23H24F3N6O [M+H]+ 457. found 457. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.76 (s, 1H), 8.60 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.11 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=5.0 Hz, 1H) 7.12 (s, 1H), 6.46 (d, J=8.8 Hz, 1H), 3.52-3.60 (m, 3H), 3.43 (m, 1H), 3.12 (m, 1H), 2.30 (s, 3H), 2.05 (s, 1H), 1.87-1.80 (m, 2H), 1.72 (s, 1H). rhSyk IC50=17 nM.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]=2[CH2:6][CH2:5]1)=[O:3].[C:23]1([C@H:29]([OH:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:21]([O:20][C:18]([CH2:17][N:8]1[C:7]2[CH2:6][CH2:5][CH:4]([C:2]([O:31][C@@H:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:30])=[O:3])[CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:19])[CH3:22]
Reactant: C[C@@H](O)c1ccccc1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CC(C(=O)Cl)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1c2c(c3ccccc31)CC(C(=O)O[C@H](C)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Crude ethyl (±)-(3-chlorocarbonyl-1,2,3,4-tetrahydro-carbazol-9-yl)-acetate (5 mmol) is dissolved in dry CH2Cl2 and treated with (R)-1-phenyl-ethanol (0.55 g, 5.4 mmol), DIEA (1.94 g, 15 mmol) and DMAP (61 mg, 0.5 mmol). The resulting yellow solution is stirred at rt overnight, diluted with EtOAc and successively washed with 0.1 N HCl, saturated aqueous NaHCO3, H2O and brine. The organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography on silica gel (hexane/EtOAc 5:1) to provide the subtitle compound as yellow oil (1.36 g) in 76% yield.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]#[N:12].C(N(CC)CC)C.[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]=2[S:10][C:2]=1[NH:1][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)#[N:12]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: N#Cc1c(N)sc2c1CCOC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(NC(=O)C(c2ccccc2)c2ccccc2)sc2c1CCOC2
Reaction time: 72 h
Yield: 37.3 %

Procedure:
To a stirred solution of 2-Amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyran (400 mg; 2.22 mmol) and triethylamine (0.93 mL; 6.66 mmol) in dry methylene chloride (10 mL) under nitrogen at room temperature was added diphenylacetyl chloride (768 mg; 3.33 mmol). After 72 h, the mixture was diluted with methylene chloride and washed with 1N HCl. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with cold diethyl ether and filtered to give 310 mg (37%) of N-(3-Cyano-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-2,2-diphenyl-acetamide as a white solid. ES-HRMS m/e calcd for C22H18N2O2S (M+H+) 375.1162, found 375.1165.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[N+:20]([C:14]1[CH:13]=[CH:12][C:11]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])([O-:22])=[O:21]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 70.4 %

Procedure:
The mixture of 2,4-difluorophenol 4 (20 g, 153.9 mmol), 5-fluoro-2nitrobenzoic acid 5, (28.5 g, 153.9 mmol), and cesium carbonate (100 g, 307.7 mmol) in DMF (310 mL) was heated in a 100° C. oil bath for 10 hrs. At the completion of the reaction, the mixture was cooled down to room temperature and was treated with 1 N HCl solution to bring pH to acidic, and was extracted with ethyl acetate. The organic layer was washed three times with 300 mL of water, dried, and concentrated to yield 32 g of 2-nitro-5-(2,4-difluorophenoxy)benzoic acid 6 as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([OH:16])=O)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].Cl.[CH:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)([CH3:20])[CH3:19].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:16])[NH:27][CH:24]3[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COC(=O)c1cnc2[nH]c(C(=O)O)cc2c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)cc2c1
Reaction time: 3 h

Procedure:
To a solution of 9.5 g 1H-Pyrrolo[2,3-b]pyridine-2,5-dicarboxylic acid 5-methyl ester in 120 mL DMF and 23.9 mL NEt3, 9.2 g 1-Isopropyl-piperidin-4-ylamine hydrochloride and 11 g BOP-Cl were added at RT and the mixture was stirred for 3 h. After addition of 20 mL of water the reaction mixture was extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with brine (1×50 ml) and then dried over MgSO4. After filtration the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with EtOAc/MeOH 9:7->EtOAc/MeOH/NH3(aq.) 6:4:0.04. The fractions containing the product were evaporated and codestilled with toluene. Yield: 7.2 g.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].Cl[P:7](=[O:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.O1CCOCC1>[NH2:2][O:3][P:7](=[O:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: NOP(=O)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To hydroxylamine hydrochloride (15.86 g, 228.2 mmol) in water (35 mL) cooled in an ice-salt bath was added 7.1 N aqueous sodium hydroxide (27.4 mL, 194.4 mmol) followed by 1,4-dioxane (100 mL). The solution was vigorously stirred for 15 min and then chlorodiphenylphosphine oxide (20.00 g, 84.52 mmol) was added as a solution in 1,4-dioxane (100 mL). The solution was stirred an additional 15 min as a white precipitate formed. The precipitate was collected and then suspended in cold (0°) 0.25 N aqueous sodium hydroxide (250 mL). The mixture was stirred for 1 h and then the solid was collected, washed with water (100 mL), and thoroughly dried under vacuum to afford the desired intermediate (7.09 g, 36%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) 7.65-7.74 (m, 4H), 7.38-7.42 (m, 6H); 31P-NMR (DMSO-d6) 23.11 (br s, 1P).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[CH:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH2:27]([NH2:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl.C(N(CC)CC)C>[CH2:27]([NH:37][C:9](=[O:11])[CH:8]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCN
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 8.0 g. of 3-phenyl-3-(3-nitrophenyl)propenoic acid in 260 ml. of methylene chloride was added 3.3 g. of triethylamine. The mixture was stirred for 20 minutes and then it was cooled in an ice-bath. To the cooled solution was added, dropwise, during 15 minutes, a solution of 3.6 g. of ethyl chloroformate in 30 ml. of methylene chloride. Stirring was continued for 20 minutes, and then a solution of 5.2 g. of decylamine in 30 ml. of methylene chloride was added, dropwise, during 10 minutes. The reaction mixture was allowed to warm to room temperature, and then it was washed successively with 1 N potassium hydroxide, 1 N hydrochloric acid, water, and saturated sodium chloride solution. The resulting solution was dried (Na2SO4) and evaporated in vacuo to give the 10.7 g. of the title compound as a oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1.O>CC(C)CC(=O)C>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCCC(O)c1ccccc1
Solvent: CC(=O)CC(C)C
Solvent: O
Solvent: Cc1ccccc1C
Product: OC(CCNC1=NCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α-(2-aminoethyl)benzylalcohol, 6.5 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred and refluxed for 3 hours with water-separator. The reaction mixture is cooled and the separated oily product is dissolved in 4-methyl-2-pentanone. The solvent is evaporated in vacuo, yielding α-{2-[N-(2imidazolin-2 -yl)amino]ethyl}benzylalcohol as a residue.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(C#C[Si](C)(C)C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 12, [5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 19) was reacted with trimethylsilylacetylene to give the title compound as dark brown gum. MS: 519.2 (MH+).
Reaction SMILES: [CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([Cl:19])[C:13](Cl)=[C:14](Cl)[C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([Cl:19])[C:13]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN=C(O)c1c(Cl)c(Sc2ccccc2)c(Sc2ccccc2)c(Cl)c1C(=O)O

Procedure:
20 g (58.65 millimols) of tetrachlorophthalic acid N-n-butylimide, 33.64 g (243 millimols) of potassium carbonate, 13.57 g (123 millimols) of thiophenol and 150 ml of tetrahydrofuran are stirred at 25° C. for 18 hours. The mixture is acidified and extracted with methylene chloride. The extracts are dried and evaporated. After recrystallisation from toluene/cyclohexane, 23.88 g (83% of theory) of 4,5-bis-(phenylthio)-3,6-dichlorophthalic acid N-n-butylimide are obtained; melting point 215°-6° C.