Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20]Cl)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.[I-].[K+].[OH-].[Na+]>CC(O)(CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[CH2:24][CH2:23][OH:22])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ncc[nH]1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: OCCc1nccn1Cc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Yield: 37.3 %

Procedure:
A mixture of 2.10 g (7.0 mmol) 2-(4-benzyloxy-phenyl)-4-chloromethyl-oxazole, 0.86 g (7.7 mmol) 2-(2-hydroxyethyl)-1H-imidazole, 1.28 g (7.7 mmol) potassium iodide and 0.31 g (7.7 mmol) sodium hydroxide in 30 ml 2-methyl-2-butanol was stirred under reflux over night. After evaporation, water was added and the residue extracted into ethyl acetate. The extract was dried, evaporated and purified on silica. Elution with ethyl acetate/methanolic ammonia 85:15 yielded 0.98 g (37%) 2-{1-[2-(4-benzyloxy-phenyl)-oxazol-4-ylmethyl]-1H-imidazol-2-yl}-ethanol as tan solid.
Reaction SMILES: [CH2:1]([O:7][C:8]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:7][C:8](=[O:9])[NH:10][C@H:11]1[C:12](=[O:14])[O:17][C@H:15]1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCOC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 71.4 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of employing (2R,3S)-2-(hexoxycarbonylamino)-3-hydroxy-butanoic acid (0.27 g, 1.10 mmol) in dry CH2Cl2 (27 mL), Et3N (0.46 mL, 3.31 mmol) and subsequently TBTU (0.42 g, 1.32 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the title compound (0.18 g, 73%), as white solid. [α]25D −25.1 (c 0.1, CHCl3). MS (ESI) m/z: 230 [M−H]+; (ESI) m/z: 228 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (t, J=6.9 Hz, 3H), 1.38-1.21 (m, 6H), 1.34 (d, J=6.4 Hz, 3H), 1.62-1.50 (m, 2H), 4.07-3.93 (m, 2H), 4.84 (dq, J=6.1, 6.4 Hz, 1H), 5.40 (dd, J=6.1, 9.3 Hz, 1H), 8.19 (d, J=9.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O)(=[O:19])=[O:18]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:23](=[O:25])[C:22]2[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:20]([S:17]([CH3:16])(=[O:18])=[O:19])[CH:21]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNc1cnccc1-c1cccnc1Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1Cl

Procedure:
The title compound was prepared in analogy to example 90, from 2-chloro-N-methyl-3,4′-bipyridin-3′-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (12%). MS (ESI): m/z=470.055 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:8])[O:6][CH3:7].[Cl:17]N1C(=O)CCC1=O.[Cl-].[NH4+]>COCCOC>[CH3:3][O:4][P:5]([CH:9]([Cl:17])[C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:8])[O:6][CH3:7]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Product: CCCCCC(=O)C(Cl)P(=O)(OC)OC
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Under argon gas atmosphere, 60% sodium hydride (1.8 g, 45.0 mmol) was suspended in anhydrous DME (10 ml) and under ice-cooling, to the suspension was added dimethyl(2-oxoheptyl)phosphonate (5.0 g, 22.5 mmol) dissolved in anhydrous DME (40 ml) and the mixture was stirred at the same conditions for 30 minutes. To the mixture was added N-chlorosuccinimide (3.0 g, 22.5 mmol) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was then added a saturated aqueous ammonium chloride solution and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified through silica gel column chromatography and further evaporated under reduced pressure to obtain dimethyl(1-chloro-2-oxoheptyl)phosphonate (4.4 g, 76%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: N#CCCNc1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(NCCC#N)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C

Procedure:
3-(2-Chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-ylamino)propanenitrile (29 mg, 0.10 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (40 mg, 0.20 mmol), cesium carbonate (64 mg, 0.20 mmol), palladium(II) acetate (3 mg, 0.01 mmol), 2-(dicyclohexylphosphino)-biphenyl (5 mg, 0.01 mmol) and dioxane (1.5 mL) were mixed in a vial and kept under an atmosphere of nitrogen. The mixture was heated in a microwave reactor at 120° C. for 90 min. The mixture was filtered through at pad of diatomeous earth. The filter plug was rinsed with MeOH. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a solid, 22 mg (48%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[C:25]([OH:26])=[CH:24][C:22]([NH2:23])=[C:21]([F:27])[CH:20]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:18][C:19]1[C:25]([OH:26])=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([F:27])[CH:20]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3cc(O)c(Cl)cc3F)c2cc1OC
Yield: 87 %

Procedure:
A mixture of 0.25 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.195 g of 4-chloro-2-fluoro-5-hydroxyaniline, 0.116 g of pyridine hydrochloride, and 3 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 10 ml of water. To this mixture was added sodium carbonate until pH 9. The product was collected, washed with water, and dried to give 0.327 g of 4-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, dec >260° C. ; mass spectrum (electrospray, m/e): M+H 373.9.
Reaction SMILES: [C:1]1([N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][NH:33]3)=[O:31])=[CH:25][CH:24]=2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C@@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:43](O)=[O:44])=[O:40]>>[CH3:37][O:38][C:39]([NH:41][C@H:42]([C:43]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:30]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:43](=[O:44])[C@H:42]([C:46]([CH3:49])([CH3:48])[CH3:47])[NH:41][C:39]([O:38][CH3:37])=[O:40])=[CH:13][CH:14]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:28][CH:27]=1)=[O:31])=[O:44])[C:46]([CH3:47])([CH3:48])[CH3:49])=[O:40]
Reactant: O=C(Nc1ccc(CN(Cc2ccc(/C=C/[C@@H]3CCCN3)cc2)c2ccccc2)cc1)[C@@H]1CCCN1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc2)c2ccccc2)cc1)C(C)(C)C
Yield: 45.8 %

Procedure:
The product from Example 149H (35 mg, 0.73 mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (33.1 mg, 0.175 mmol) were processed using the method described in Example 43 to afford 33 mg (55%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.98 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.17 (m, 4H), 7.06 (m, 3H), 6.63 (m, 2H), 6.55 (t, J=7.3 Hz, 1H), 6.37 (d, J=15.7 Hz, 1H), 6.22 (m, 1H), 6.17 (dd, J=16.0, 6.3 Hz, 1H), 4.63 (m, 1H), 4.61 (s, 2H), 4.58 (s, 2H), 4.42 (m, 1H), 4.19 (m, 2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.63 (m, 2H), 3.52 (s, 6H), 2.16 (m, 2H), 1.96 (m, 2H), 1.84 (m, 4H), 0.95 (s, 9H), 0.93 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: [O-][n+]1c(Cl)cccc1Oc1ccccc1

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.47 g (0.0050 moles of phenol was reacted with 0.200 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 6 hours to give 2-chloro-6-phenyloxypyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 3.5 hours to give 1-hydroxy-6-phenyoxypyridine-2-(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCl to pH 3. The water solution was extracted with dichloromethane (2×25 ml) and was dried over sodium sulfate. The dichloromethane solution was stripped in vacuo to give 1.29 g which was purified with Flash Chromatography (9:1 ethyl acetate:methanol):0.82 (65%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1.C(O)(=O)C.I>O>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2ccc(F)cc2C)cc1
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1-c1ccc(O)cc1

Procedure:
To a solution of 2.1 grams of 4-(2'-methyl-4'-fluorophenyl)-anisole in 50 ml. of boiling acetic acid is added 5 ml. of hydriodic acid and the boiling continued for 3 hours. Water is added and the reaction mixture cooled and the 4-(2'-methyl-4'-fluorophenyl)-phenol crystallizes. Further purification is then achieved by recrystallization of the solid from aqueous ethanol to yield 4-(2'-methyl-4'-fluorophenyl)-phenol.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:15]2[CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1

Procedure:
To 3-bromopyridine (8.53 g, 54 mmol) in ethyleneglycol dimethylether (180 ml) is added 3-nitrophenylboronic acid (10 g, 59.95 mmol), aqueous potassium carbonate (90 ml, 2M) and tetrakis(triphenylphosphine)palladium (0.5 g, 0.43 mmol). The mixture is refluxed gently in a nitrogen atmosphere overnight. The cooled reaction mixture is filtered and water (600 ml) is added to the filtrate. The precipitate is filtered off and washed with water. This crude product is dissolved in hot water (400 ml) with addition of hydrochloric acid (25 ml, 4 M). The mixture is filtered while still hot. The filtrate is cooled in an ice bath and pure 3-(3-pyridyl)-nitrobenzene is precipitated by addition of 12 M NaOH. Yield 9.14 g (85%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Yield: 91.2 %

Procedure:
A mixture of 4-fluorobenzaldehyde (10 gm, 0.08 moles) and N-methylpiperazine (14 gm, 0.14 moles) in water (80 mL) containing sodium carbonate (12.7 gm, 0.12 moles) was stirred and refluxed for 21 hours. After cooling, the mixture was poured into a separatory funnel containing water (200 mL) and the oily product was extracted into methylene chloride (3×50 mL). The combined extracts were washed with water and were then stripped under vacuum. The product, which was isolated as an oil, solidified into a tan solid upon cooling. The solid product was triturated in hexane and isolated by filtration. After drying, there was obtained 14.9 gm (91%) of N-(4-formylphenyl)-N′-methylpiperazine as an off white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:9]=2[N:8]=1>>[Cl:3][CH2:6][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:9]=2[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cccc2[nH]c(CO)nc12
Product: O=[N+]([O-])c1cccc2[nH]c(CCl)nc12

Procedure:
Thionyl chloride (8.3 ml) was added dropwise to 2-hydroxymethyl-4-nitro-1H-benzimidazole (1.15 g) at 0° C. and the suspension was then heated at reflux for 3 hours. The excess of thionyl chloride was removed in vacuo, and the residue was poured into ice and adjusted to pH 7 with saturated sodium bicarbonate aqueous solution. The precipitate was collected by vacuum filtration and washed water to give 2-chloromethyl-4-nitro-1H-benzimidazole (1.32 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]([CH2:18][OH:19])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[C:25](OCCBr)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([O:19][CH2:18][C:9]1[C:8]([CH:20]([CH3:22])[CH3:21])=[N:7][N:6]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCCBr
Reactant: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(C(C)C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of (7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl)methanol (40 mg) in N,N-dimethylformamide (1 mL) was added 40% sodium hydride in oil (5.5 mg) in an ice-water bath. After 20 minutes, to the mixture was added 2-bromoethyl acetate (31 mg) at the temperature. After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=10-1) to give [7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl acetate as a pale yellow solid (42 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN(C)C.[NH2:47][CH2:48][C:49]1[C:50](=[O:58])[NH:51][C:52]([CH3:57])=[CH:53][C:54]=1[O:55][CH3:56]>ClCCl.O>[CH3:56][O:55][C:54]1[CH:53]=[C:52]([CH3:57])[NH:51][C:50](=[O:58])[C:49]=1[CH2:48][NH:47][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:2]=1[CH3:1])=[O:12]
Reactant: COc1cc(C)[nH]c(=O)c1CN
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylic acid (66 mg, 0.24 mmol) in anhydrous dichloromethane (5 mL) was added N-hydroxybenzotriazole (38 mg, 0.29 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (55 mg, 0.29 mmol) and trimethylamine (36 mg, 0.36 mmol), and stirred at room temperature for 0.5 hour, 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one (40 mg, 0.24 mmol) was added and stirred at room temperature for 16 hours. To the reaction mixture was added water (10 mL), extracted with dichloromethane (10 mL) 2 times, combined and concentrated the organic layers, the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxamide as an off-white solid (0.08 g, 52%). LRMS (M+H+) m/z: calcd 429.21. found 429.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Br:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Yield: 98.2 %

Procedure:
21.8 g (57.9 mmol) of ethyl (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto [2,1-c]imidazo [1,5-a][1,4]benzodiazepine-1-carboxylate were heated to reflux for 15 minutes with 17 ml of 4N sodium hydroxide solution and 200 ml of ethanol. 17 ml of 4N hydrochloric acid and 250 ml of water were added at room temperature. The alcohol was evaporated and the suspension was cooled to 0°. By suction filtration and drying the crystals there were obtained 19.8 g (98%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylic acid of m.p. 178°-180°.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:23]([OH:26])[C:24]#[CH:25]>C(N(CC)CC)C.CN(C=O)C.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>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:25]#[C:24][CH2:23][OH:26])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: C#CCO
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(C#CCO)cc2s1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
120 mg (0.30 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A), 10.5 mg (0.01 mmol) of PdCl2(PPh3)2 and 4.6 mg (0.02 mmol) of copper(I) iodide are dissolved in 1.5 ml of triethylamine/DMF (2:1) under argon and stirred at 60° C. for 1 h. Addition of 25.1 mg (0.45 mmol) of propargyl alcohol is followed by heating at 70° C. for a further 16 h. Cooling is followed by filtration through kieselguhr and purification by preparative HPLC, concentration and drying of the product under high vacuum. 12 mg (11% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.S(Cl)(Cl)=O.[F:14][C:15]([F:32])([F:31])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([NH2:30])=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=1.N1C(C)=CC=CC=1C>C(OC(=O)C)(C)C>[NH2:30][C:24]1[N:25]=[C:26]([NH:29][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:9])[CH:27]=[CH:28][C:23]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:15]([F:32])([F:14])[F:31]
Reactant: Cc1nocc1C(=O)O
Reactant: Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)OC(C)C
Solvent: O=S(Cl)Cl
Product: Cc1nocc1C(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a suspension of 3-methylisoxazole-4-carboxylic acid (2.58 g, 20 mmol) in isopropylacetate (26 ml) was added thionyl chloride (2.4 g, 1.47 ml, 20 mmol) and the reaction heated to 70° C. for 5 hours before cooling to room temperature. 11/12ths of this solution was added dropwise to a solution of 3-[2-(trifluoromethoxy)phenyl]pyridine-2,6-diamine (Preparation 2, 4.56 g, 16.9 mmol) and 2,6-lutidine (3.98 g, 4.3 ml, 37.2 mmol) in isopropylacetate (23 ml). The reaction was stirred at room temperature for 30 minutes during which a slurry was formed caused by crystallisation of lutidine hydrochloride. 20% w/w citric acid (46 ml) was added, the biphasic mixture stirred for 10 minutes before separation. The organic phase was washed with saturated sodium bicarbonate solution (46 ml), water (46 ml) and then reduced in volume to 16 ml. Toluene was then added (2×46 ml) and the volume reduced again to 20 ml. The resultant white solid was collected by filtration, washed with toluene (10 ml) and dried to afford the title compound in 46% yield. The white solid (2.1 g) was slurried in toluene (10 ml, 5 ml/g) and heated to reflux to form a solution. The resultant solution was cooled to 0° C. and granulated for 1 hour. The solid was collected by filtration, washed with toluene (6 ml, 3 ml/g) and dried overnight to yield 1.8 g of crystalline material.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:25]O)=[N:18][C:19]=1[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:2][CH2:25][C:17]1[N:18]=[C:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[F:5])=[CH:15][CH:16]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CBr)nc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Phosphorus tribromide (112 μL) was added to DMF (3.0 mL) at 0° C., and the mixture was stirred at 0° C. for 20 min. To the obtained white suspension was added a solution of (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (300 mg) in DMF (1.0 mL), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (255 mg) as a pale-yellow oil.