Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:2]/[C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Product: CCOC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1

Procedure:
A mixture of ethyl 4-acetylbenzoate (3.00 g, 15.62 mmol) and N,N-dimethylformamide dimethyl acetal (6.2 g, 52.10 mmol) was refluxed for 18 hours, cooled and concentrated to give ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate quantitatively. A solution of ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate, potassium carbonate (3.55 g, 25.74 mmol), and 4-(amidinoamino)benzamide (3.10 g, 12.87 mmol) in ETOH (120 mL) was refluxed for 18 hours. The mixture was cooled, filtered, and washed with ETOH, water, then ether respectively to give ethyl 4-{2-[(4-carbamoylphenyl)amino]pyrimidin-4-yl}benzoate (2.60 g, 46% yield). This compound was refluxed for 2 hours in ETOH (30 mL), water (20 mL), and NaOH (0.640 g, 16 mmol). The reaction mixture was cooled, acidified to pH 3, and filtered to give 1.00 gram (42% yield) of the titled compound. HPLC/ES-MS (20-100% acetonitrile): R.T. 4.7 min. (Method A); (m/z) 335 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:20]=[CH:19][C:18]2OC3C(=CC=CC=3)NC=2C=1.[NH2:21][CH2:22]CC1CCCN1C.[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:20][CH2:19][CH2:18][N:21]1[CH3:22]
Reactant: CN1CCCC1CCN
Reactant: c1ccc(-c2ccc3c(c2)Nc2ccccc2O3)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCCC1c1ccccn1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
2-Pyridinyl phenoxazine (28 mg,), 2-(2-aminoethyl)-1-methylpyrrolidine (17 ul, 0.1173 mmol) and aluminum chloride (21 mg, 0.1575 mmol) were mixed in anhydrous dichloromethane (1 ml) and stirred for 1 h. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3×10 ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 2-pyridinyl methylpyrrolidine (17.5 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14]
Reactant: CC(C)(O)CCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(O)CCOc1cccc([N+](=O)[O-])c1C#N
Yield: 81 %

Procedure:
Prepared as in Example 215c from 3-methylbutane-1,3-diol and 2,6-dinitrobenzonitrile in 81% yield. MS 251 (MH+).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.CO.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C@@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])[C@@H:43]([C:54]([OH:56])=[O:55])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[CH3:1][O:55][C:54]([C@@H:43]1[C@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])[CH2:45][CH2:46][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:40])[CH2:42]1)=[O:56]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (2.66 g) in THF (30 ml) was added diethyl azodicarboxylate (1.58 mL) at 0° C. After 30 minutes, methanol (1.58 mL) and a solution of (3R,4R)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester in THF (30 mL) were added subsequently at 0-5° C. The reaction mixture was stirred for 3 h at room temperature. The reaction was quenched with a saturated aqueous solution of NH4Cl, tert-butyl methyl ether was added, and the phases were separated. The inorganic one was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, CH2Cl2 to CH2Cl2/MeOH 95:5) yielded (3R,4R)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a colorless gum, MS: 334.1 ([M+H])+.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:10](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:8][C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(N)c1ccncc1
Reactant: N#CC(C#N)=Cc1ccccc1
Product: NCc1c(N)nc(-c2ccncc2)nc1-c1ccccc1

Procedure:
The title compound, MS: m/e=278.0 (M+H+), was prepared from isonicotinamidine and 2-benzylidene-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([C:15](=[CH2:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.[H][H]>[OH-].[Na+].[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: [H][H]
Reactant: C=C(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Yield: 71.4 %

Procedure:
2.5 g of 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)acrylic acid is dissolved in 20 ml of 0.5 N aqueous sodium hydroxide soution, and 1 g of Raney nickel is added. The solution is stirred in a hydrogen stream at ordinary pressure and temperature until absorption of 230 ml of hydrogen is attained. The Raney nickel is removed by filtration, and the filtrate is neutralized with hydrochloric acid. The resulting crystalline precipitate is filtered off, washed with water, and recrystallized from aqueous dioxane to give 1.8 g of 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid melting at 183°-184°C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]([O:13][C:14](=[O:36])[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:33][CH2:34][CH3:35])([CH3:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:9]([O:13][C:14](=[O:36])[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:33][CH2:34][CH3:35])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C(Cl)c1cccs1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccs3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophene-2-carbonyl chloride (38 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C28H31N3O3S+H: 490, observed: 490.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1>Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nnc(Nc3ccccc3F)o2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)c1nnc(Nc2ccccc2F)o1
Reaction time: 18 h
Yield: 65.7 %

Procedure:
tert-Butyl 4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]piperidine-1-carboxylate (5.66 g, 13.96 mmol) was suspended in 4M HCl in 1,4-dioxane (50 ml) and stirred for 18 hours. After removal of the solvent in vacuo the residue was partitioned between MeOH:DCM (1:9) (500 mL) and 2M aqueous potassium carbonate (500 mL). The aqueous was extracted with MeOH:DCM (1:9) (7×50 mL) and the combined organics dried (Na2SO4), filtered and concentrated in vacuo. The solid was triturated with hot Et2O (20 mL), filtered then washed with Et2O (20 mL), hexane (20 mL) to leave the title product (Intermediate 101, 2.80 g, 66%) as a beige powder; 1H NMR δ1.44-1.57 (2H, m), 1.66-1.74 (2H, m), 2.47-2.59 (2H, m), 2.94-3.02 (2H, m), 3.74-3.86 (1H, m), 7.04-7.11 (1H, m), 7.17-7.28 (2H, m), 7.96-8.04 (1H, m), 8.92 (1H, d); MS m/e (MH)+ 306.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[C:10]([OH:12])[CH:11]=1)([O-:5])=[O:4].[C:20]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]OS(C)(=O)=O)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[OH-].[Na+]>[C:20]([N:27]1[CH2:28][CH2:29][CH:30]([CH2:33][O:12][C:10]2[C:9]([C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:11]=2)[CH2:31][CH2:32]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 60% NaH suspension in DMF (30 mL) at RT added a solution of 5-nitro-2-pentafluoroethyl-phenol (3.6 g) in 5 mL DMF. The dark red mixture was stirred at RT for 10 min then added a solution of 1-Boc-4-methylsulfonyloxymethyl-piperidine (3.1 g) in 5 mL DMF. The reaction was stirred at 60° C. and 95° C. After 1 h, added 2.94 g K2CO3 and stirred overnight at 105° C. After cooling to RT, the reaction was diluted with hexanes and 1N NaOH. Separated layers, and washed organic layer with 1N NaOH and with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification with silica gel column chromatography with 8% EtOAc/Hexanes yielded 1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine as a light yellow thick oil.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9](\[NH:17][C:18]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:19]=2)/[N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15]O)=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:17][C:18]3[N:22]([N:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH:19]=3)[CH2:15][C@@H:11]3[CH2:12][CH2:13][CH2:14][N:10]\23)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(/N=C(\Nc1cc(-c2ccc(F)cc2)n[nH]1)N1CCC[C@H]1CO)c1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(/N=C1\Nc2cc(-c3ccc(F)cc3)nn2C[C@@H]2CCCN12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of (S,E)-4-fluoro-N-(((3-(4-fluorophenyl)-1H-pyrazol-5-yl)amino)(2-(hydroxymethyl)pyrrolidin-1-yl)methylene)benzamide (30 mg, 0.07 mmol) in anhydrous THF (0.4 mL) under a nitrogen atmosphere was added triphenylphosphine (22 mg, 0.085 mmol) followed by DIAD (16 μL, 0.085 mmol). The reaction mixture was stirred at room temperature for 30 minutes and purification by silica chromatography (EtOAc:hexanes) provided the title compound (22 mg, 77% yield). LCMS (ESI). found (M-H), 406.06. HPLC (Method A): 7.11 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:23][O:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:17]=[C:18]([C:30]5[C:25]([O:24][CH3:23])=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:19]=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ncccc1B(O)O
Reactant: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ncccc1-c1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 110 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide (36 mg, 0.10 mmol) was dissolved in 1 mL of ethanol containing 0.12 mL of a 2 M aqueous solution of potassium carbonate, 2-methoxypyridin-3-ylboronic acid (18 mg, 0.12 mmol) and 6 mg of Fibre-Cat 1007. The reaction mixture was then heated to 110° C. for 10 minutes in a microwave reactor. The resulting material was cooled to room temperature, filtered, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product. ESI-MS m/z calc. 389.1. found 390.1 (M+1)+. Retention time 3.09 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:38][C@@H:39]([OH:42])[C:40]#[CH:41]>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:41]=[C:40]([C@H:39]([OH:42])[CH3:38])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#C[C@@H](C)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)c1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (39.2 mg), CuI (12.8 mg), and Et3N (0.16 mL) in CHCl3 (5.6 mL) is added (R)-(+)-3-butyn-2-ol (0.053 mL). The reaction is stirred at room temperature for 2 days. The reaction is condensed to remove CHCl3. The solvent is replaced with ETOH (5.6 mL) and additional Et3N (0.16 mL) is added to the reaction mixture. N2 is passed over the surface and the reaction is heated at 60° C. overnight, then allowed to cool to room temperature. The reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2. Product-containing fractions are combined, condensed, and recrystallized from hot acetonitrile to afford 33.8 mg (13%) of N-(4-chlorobenzyl)-2-[(1R)-1-hydroxyethyl]-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:31]=[CH:30][C:22]2[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=2[CH:20]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[N:18]/[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:28])([CH3:29])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: O=Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(=O)c2cc(/N=C/c3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Yield: 92.4 %

Procedure:
A solution of 4-[(4-chlorophenyl)ethynyl]benzaldehyde (2.60 g, 10.9 mmol, intermediate which may be prepared according to methods disclosed in EP03103780.7) and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (2.00 g, 10.36 mmol) in toluene (40 mL) was heated at reflux for 2 hrs with azeotropic removal of water. Then the temperature was cooled down slowly. A yellow solid precipitated out and MeOH (40 mL) was added. The precipitate was filtered, washed with MeOH (2×) and dried under reduced pressure to give 3.98 g (92%) of the title compound as a yellow powder. 1H NMR (CDCl3) δ: 8.53 (s, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.85 (d, J=2.5 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.53 (dd, J=8.6, 2.5 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:10])=[C:6]([CH3:9])[C:7]=1[CH3:8].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O>C(O)C>[Cl:10][C:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:2]2[N:3]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:1]=2)[N:4]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Cc1c(N)nnc(Cl)c1C
Solvent: CCO
Product: Cc1c(Cl)nn2cc(-c3ccc(F)cc3)nc2c1C
Yield: 81.9 %

Procedure:
A solution of 13 g (85 mmol) of 3-amino-6-chloro-4.5-dimethylpyridazine and 23 g (107 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone in 130 mL of ethanol is refluxed for 16 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in chloroform. The organic phase is washed with diluted aqueous ammonia, dried over sodium sulfate and concentrated under reduced pressure to give a brown solid. This solid is triturated in acetone to give 19.2 g of a beige-colored powder.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[CH:4][C:5]([F:14])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C1(C)C=CC=CC=1.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>[F:14][C:5]1[CH:4]=[C:3]([F:15])[C:2]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)=[CH:7][C:6]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: OB(O)c1ccncc1
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: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1cc(-c2ccncc2)c(F)cc1F
Temperature: 90 °C

Procedure:
5-Bromo-2,4-difluoro-N,N-dimethyl-benzenesulfonamide (400 mg) and 4-pyridine-boronic acid (165 mg) was dissolved in toluene (5 ml) and abs EtoH (5 ml). To the mixture was then added Na2CO3 (200 mg) and Pd(PPh3)4 (79 mg) under an atmosphere of Argon. The resulting mixture was heated to 90° C. for 18 h. Then CH2Cl2 was added and the organic phase was washed with water and dried (MgSO4), filtered and evaporated to dryness. The residue was then used without any further purification. (MS m/z (rel. intensity, 70 eV) 298 (M+, 77), 256 (36), 191 (bp), 190 (98), 143 (74).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH3:22])[C:14](=[O:20])[CH2:15]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-one (550 mg, 1.75 mmol) in THF (2 mL) at −78° C. was added LiHMDS in THF (2.62 mL, 1.0 M in THF, 2.62 mmol) dropwise over 15 min. The resulting mixture was allowed to stir at −78° C. for 30 min before the addition of MeI (1.24 g, 8.75 mmol). The reaction mixture was stirred at −78° C. for 2.5 h before it was allowed to warm up to room temperature for 15 min. The reaction mixture was quenched by the addition of a saturated aqueous NH4Cl solution (25 mL) and EtOAc (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified via silica gel chromatography to give 9-(4-chloro-benzenesulfonyl)-2-methyl-9-aza-bicyclo[3.3.1]nonan-3-one as a white solid. Retention time (min)=2.13 min, Method [1], MS (ESI) 350 (M+Na).
Reaction SMILES: N[C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1.N1CC[C@@H]([OH:30])C1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[OH:30][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](N)C3)cc2)cc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](O)C3)cc2)cc1
Yield: 69 %

Procedure:
4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile (200 mg, 0.74 mmol), (3R)-3-pyrrolidinol (70 mg, 0.81 mmol), potassium carbonate (152 mg) and potassium iodide (183 mg) in 25 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (69 % yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11][NH:12][S:13]([C:16]2[CH:21]=CC(C)=CC=2)(=O)=O)CC)=[CH:4][CH:3]=1.[OH-].[Na+]>S(Cl)(Cl)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:11]=[N:12][S:13][C:16]=2[CH3:21])=[CH:6][CH:7]=1
Reactant: CCC(=NNS(=O)(=O)c1ccc(C)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: Cc1snnc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
N′-[1-(4-Fluorophenyl)propylidene]-4-methylbenzenesulfonohydrazide (12.0 g) was dissolved in thionyl chloride (30 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into a 1N aqueous sodium hydroxide solution. The precipitated solids were collected by filtration, washed with water and dried with airflow to give 4-(4-fluorophenyl)-5-methyl-1,2,3-thiadiazole (6.19 g, 65%) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[CH2:51]>CN(C)C=O>[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[CH:51][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: C=Cc1ccccc1Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C1Nc2cccc(/C=C/c3ccccc3Cl)c2/C1=C/c1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(C=Cc3ccccc3Cl)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (39 mg, 0.116 mmol) (from Example 71 above), triethylamine (65 μL, 0.464 mmol), tri-o-tolylphosphine (7 mg, 0.023 mmol) (Aldrich), palladium(ll) acetate (2 mg, 0.009 mmol) (Aldrich), and 2-chlorostyrene (24 mg, 0.173 mmol) (Aldrich) in 3 mL of dry N,N-dimethylformamide was heated at 85° C. under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 5% ethyl acetate-benzene elution) to yield pure 4-[(E)-2-(2-chlorophenyl)-ethenyl]-1,3-dihydro-(Z)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow solid. (Yield 27 mg, 67%; mp=257-258° C.).