Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:47][C:44]4[CH:45]=[CH:46][C:41]([N:38]5[CH2:39][CH2:40][CH:35]([CH2:34][N:31]6[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]6)[CH2:36][CH2:37]5)=[CH:42][CH:43]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(CC2CCN(c3ccc(N)cc3)CC2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(CC2CCN(c3ccc(Nc4ncc5ccc(-c6cccc(S(=O)(=O)NC(C)(C)C)c6)n5n4)cc3)CC2)CC1
Yield: 25.4 %

Procedure:
N-tert-Butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (0.1 g, 0.3 mmol), 4-[4-(4-Methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-phenylamine (147 mg, 0.510 mmol), N,N-Diisopropylethylamine (0.124 mL, 0.712 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were heated in the microwave at 225° C. for 30 minutes. The reaction was concentrated and redissolved in 3 ml of DMSO and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate, extracted with DCM, dried filtered and concentrated to give a yellow solid (47 mg, 30%). MP 233-235° C. LCMS (E/I+) 485 (M+H). NMR 1H (DMSO-d6)-9.26 (s, 1H), 8.98 (s, 1H), 8.54 (s, 1H), 8.38 (d, 1H, J=8.04 Hz), 7.84 (d, 1H, J=7.90 Hz), 7.73 (t, 1H, J=7.81 Hz), 7.57-7.61 (m, 3H), 7.16 (d, 1H, J=4.52 Hz), 6.93-6.97 (m, 3H), 3.58 (d, 2H, J=11.59 Hz), 2.54-2.62 (m, 2H), 2.28-2.38 (m, 6H), 2.14 (m, 6H), 1.77 (d, 2H, J=12.50 Hz), 1.55-1.65 (m, 1H), 1.16-1.26 (m, 3H), 1.12 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:21][CH3:22])=[O:12])=[O:8])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC(=O)c1ccc(OC)cc1

Procedure:
21 g of 3-(4-methoxybenzoyl)propionic acid were heated under reflux for 51/4 hours in 350 ml of ethanol after addition of 7.3 ml of concentrated sulfuric acid The reaction mixture was worked up by concentrating it, taking up the remaining residue in 100 ml of water and extracting the mixture with dichloromethane. The organic phase was separated, washed with 50 ml of saturated aqueous sodium bicarbonate solution, then washed with water until neutral, dried and concentrated. 23.3 g of crude ethyl 3-(4-methoxybenzoyl)-propionate were obtained as a yellowish, crystallizing oil.
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:6]=[CH:7][C:8]=1[CH2:9]C.[C:19]([O-])(=[S:21])[CH3:20].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([O:32][C:33]([C:35]1[C:40]([CH2:41]Br)=[N:39][CH:38]=[CH:37][N:36]=1)=[O:34])[CH3:31]>C(O)C>[CH2:30]([O:32][C:33]([C:35]1[C:40]([CH2:41][S:21][CH2:19][C:20]2[CH:7]=[CH:6][C:5]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[CH:4][C:3]=2[CH2:8][CH3:9])=[N:39][CH:38]=[CH:37][N:36]=1)=[O:34])[CH3:31]
Reactant: CCOC(=O)c1nccnc1CBr
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1CBr
Reactant: CC([O-])=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1nccnc1CSCc1ccc(-c2ccc(Cl)cc2Cl)cc1CC
Reaction time: 1 h

Procedure:
To a solution of 3′-bromomethyl-2,4-dichloro-4′-ethyl-biphenyl (1 g) in ethanol (10 ml) was added potassium thioacetate (1.1 g, Aldrich 241776) and the mixture stirred for 1 hr. To this mixture was added potassium carbonate (0.442 g) and stirring was continued for a further hour. A solution of 3-bromomethyl-pyrazine-2-carboxylic acid ethyl ester (0.712 g) in ethanol (3 ml) was added to the reaction mixture and the reaction was stirred for a further 18 hr. The reaction was partitioned between chloroform and water. The organic layer was concentrated and the residue purified by chromatography on silica gel (eluent: 0-20% v/v ethyl acetate in dichloromethane) to give a 30% pure sample of 3-(2′,4′-dichloro-3-ethyl-biphenyl-4-ylmethylsulfanylmethyl)-pyrazine-2-carboxylic acid ethyl ester contaminated with 3-bromomethyl-pyrazine-2-carboxylic acid ethyl ester (0.300 g). MH+=461, RT=2.25 min (Method A).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[N:26][N:27]([CH3:34])[C:28]3=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Reactant: Cn1ncc2c(N)cccc2c1=O
Agent: [Ti+4]
Agent: CC[O-]
Product: CCC(CC(O)(C=Nc1cccc2c(=O)n(C)ncc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 29, 265 mg (0.86 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 150 mg (0.86 mmol) of 5-amino-2-methylphthalazin-1-one and 0.42 ml of titanium tetraethoxide are reacted to give 5-{[4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}-2-methylphthalazin-1-one. 410 mg of crude imine are cyclized in the same way as in Example 29 at −20° C. with 3.5 ml (3.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) and subsequent preparative thin-layer chromatography on silica gel with dichloromethane/methanol 9:1 yield 10 mg of product and 8.6 mg of the 8α compound (Example 45).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:16][C:15]2[CH:17]=[CH:18][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(NC(=N)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 4-fluorobenzonitrile (2.176 g, 17.98 mmol) and 4-methylthioaniline (2.5 g, 17.98 mmol) by following the procedure described in preparation 1, (2.06 g, 44.1%, purity 98.8% by HPLC), mp 121-124° C. 1H-NMR (CDCl3):δ 2.48 (s, 3H), 4.82 (bs, 2H, D2O exchangeable), 6.91-6.93 (d, 2H), 7.1-7.14 (m, 2H), 7.26-7.30 (m, 2H), 7.86 (bs, 2H). MS m/z:261.1(M+)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C(Cl)[O:22][C:23](Cl)(Cl)Cl.[CH4:28]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:19])[C@@H:10]([NH:11][C:23]([N:11]1[CH2:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:28]1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)N1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 166.1 %

Procedure:
A solution of phenylalanine benzyl ester (8.80 g, 23.4 mmol) in toluene was treated with diphosgene (4.63 g, 23.4 mmol) and activated charcoal (100 mg). The resulting suspension was heated at reflux for 4.5 hours then cooled to room temperature and stirred overnight. The reaction mixture was filtered through celite and concentrated. The residue was dissolved in EtOAc, cooled to 0° C. and treated with hexamethyleneimine (2.32 g, 23.4 mmol) and stirred for 2 hours. Additional hexamethyleneimine (1.0 mL) was added and the reaction mixture warmed to room temperature and stirred overnight. The reaction mixture was washed with 1N HCl solution, brine, dried (MgSO4) and concentrated. The residue was purified by chromatography (silica gel, gradient elution 4:1 hexane/EtOAc to 1:1 hexane/EtOAc) to give the title compound as a white solid (3.94 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH3:16])=[CH:4][CH:3]=1.[CH2:19]=[O:20]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][CH2:19][OH:20])=[CH:17][CH:18]=1
Reactant: C=O
Reactant: Cc1ccc(Cn2c(C)nc3ccccc32)cc1
Solvent: c1ccncc1
Product: Cc1ccc(Cn2c(CCO)nc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Next, 1-(4-methylbenzyl)-2-(2-hydroxyethyl)benzimidazole was prepared. A mixture of 1-(4-methylbenzyl)-2-methylbenzimidazole (5.1 g, 21 mmol), formaldehyde (82 mmol as 6.7 g of the 37% aqueous solution), and 6.5 g of pyridine were stirred magnetically and heated to 90° C. After 24 h, the mixture was cooled to ambient and concentrated at reduced pressure to deposit a tan oil. The product was purified by flash chromatography (silica gel, 75% dichloromcthane/25% ether), followed by recrystallization from a mixture of 15 mL of methanol plus 10 mL of water. The product was obtained as 1.5 g (41%) of a white solid. 1H NMR (CDCl3)δ 2.31 (s, 3H), 2.99 (t, J=5.4, 2H), 4.12 (t, J=5.4, 2H), 4.4 (br s, 1H), 5.29 (s, 2H), 6.94 (d, J=8.0, 2H), 7.10 (d, J=7.9, 2H), 7.25 (m, 3H), 7.73 (m, 1H). ES−MS m/e 267+ (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4](/[N:10]=[C:11]2\[N:12]([C:27]#[N:28])[CH2:13][C@@H:14]3[C@H:18]([O:19][Si](C(C)(C)C)(C)C)[CH2:17][CH2:16][N:15]\23)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CC=CC=1.C1C[O:39]CC1>>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4](/[N:10]=[C:11]2\[N:12]([C:27]([NH2:28])=[O:39])[CH2:13][C@@H:14]3[C@H:18]([OH:19])[CH2:17][CH2:16][N:15]\23)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C1CCOC1
Reactant: Cc1c(/N=C2\N(C#N)C[C@@H]3[C@H](O[Si](C)(C)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Solvent: c1ccncc1
Product: Cc1c(/N=C2\N(C(N)=O)C[C@@H]3[C@H](O)CCN23)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 12A (30.0 mg, 0.0699 mmol) was dissolved in THF (1 mL) and HF/pyridine (˜2.3:1, 0.075 mL) was added. After stirring at rt overnight, the reaction was concentrated and purified via preparative HPLC (YMC ODS C-18, 21.2×100 mm, eluting with 50-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm. The peaks were collected, combined and repurified via preparative HPLC (YMC ODS C-18, 21.2×100 mm, eluting with 30-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm to provide compound 12B (8.0 mg) as a clear film. MS: m/z 334 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][O:8][CH2:9][Cl:10]>ClC=C(Cl)Cl>[Cl-:10].[CH3:7][O:8][CH2:9][N:4]1[CH:5]=[CH:6][N+:2]([CH3:1])=[CH:3]1
Reactant: COCCl
Reactant: Cn1ccnc1
Solvent: ClC=C(Cl)Cl
Product: COCn1cc[n+](C)c1
Product: [Cl-]
Yield: 103.2 %

Procedure:
Into a 500 mL round-bottomed flask equipped with a stir bar, Argon inlet and addition funnel was dissolved 1-methylimidazole (25 g, 0.31 mol) in trichloroethylene (100 mL). With stirring chloromethyl methyl ether (35 g, 0.43 mol) was added slowly dropwise over a 0.5 h period. The mixture warmed and a turbid, two-layer mixture formed upon addition. The mixture was refluxed 2 h, cooled and poured into a separatory funnel. The organic layer was separated, filtered and the solvent was removed under vacuum at 45° C. to yield a tan-beige viscous liquid (52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:34])([F:33])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:33])[F:34])=[CH:17][CH:18]=1)[S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: O=[N+]([O-])c1ccccc1SNc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N(Sc1ccccc1[N+](=O)[O-])c1ccc(OC(F)(F)F)cc1)c1ccccc1Cl
Temperature: -5 °C
Reaction time: 96 h

Procedure:
A solution of 50 g of 2-chlorobenzoyl isocyanate in 50 ml of dry toluene was added to a stirred solution of 60 g of N-[4-(trifluoromethoxy)phenyl]-2-nitrobenzenesulphenamide in 100 ml of the same solvent. The reaction was slightly exothermic, reaching a maximum temperature of 35° C. After 4 days at room temperature, the reaction mixture was cooled to -5° C. and the crystalline cake of product was broken up under cold toluene, filtered, washed with toluene followed by cold light petroleum (b.p. 40°-60° C.) and dried at 40° C. under reduced pressure, to give 1, as pale yellow crystals, m.p. 155°-158° C. (with decomposition).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[C:14]([OH:17])(=O)[CH3:15].O.[C:19](#N)[CH3:20]>>[CH2:6]([CH:20]1[CH2:19][CH2:5][C:4]2[C:15](=[CH:8][CH:9]=[CH:2][CH:3]=2)[C:14]1=[O:17])[C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: CC(=O)O
Reactant: CC#N
Reactant: Fc1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1c2ccccc2CCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-Fluorobenzyl bromide (20.7 g, 109 mmol) was added to a solution of the enamine in acetonitrile (200 mL) which had been dried over 4A molecular sieves. This mixture was heated at reflux under nitrogen for 3 days. After cooling, the reaction mixture was concentrated in vacuo to provide a brown solid. Chloroform (25 mL), glacial acetic acid (50 mL), and water (200 mL) were added to this material and the resulting mixture was stirred at ambient temperature for 20 h. Additional chloroform was added to the reaction mixture, and the layers were separated. The organic layer was washed with water, dried (Na2SO4), and concentrated to give 24.2 g of the corresponding -benzyl--tetralone as a dark brown oil. This material was purified on a flash silica gel column (25% hexanes-chloroform) to provide 17.9 g of a red oil which was purified further on a flash silica gel column (1:1 hexanes-chloroform) to provide 12.1 g (70%) of desired product, 1-(4-fluorobenzyl)--tetralone, as a yellow oil. MS (CI-CH4), m/z 255 (MH+). 1H NMR (CDCl3) 2.38-2.56 (m, 3H), 2.76-2.86 (m 1H), 3.21 (AB octet, J=15.5, 6.8 Hz, 2H), 3.70 (t, J=6.2 Hz, 1 H), 6.75-6.85 (m, 4H), 6.93 (dd, J=7.5, 2.8 Hz, 1H), 7.09-7.22 (m, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.Cl.[C:37]([C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)(=[NH:39])[NH2:38].C([O-])(=O)C.[Na+]>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:39][C:37]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=3)=[N:38]2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: N=C(N)c1ccncc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCCc1ccccc1)C1=C(COCCN2CCCCC2)NC(c2ccncc2)=NC1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 3.1 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (1.50 g, 4.32 mmol), 3,4-dichlorobenzaldehyde (0.907 g, 5.18 mmol), 4-amidinopyridine hydrochloride (0.816 g, 5.18 mmol) and sodium acetate (0.425 g, 5.18 mmol) was stirred in N,N-dimethylformamide (10 mL) for 14 days at room temperature and then heated to 60° C. for 6 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography to give the title compound (81.7 mg) as an oil.
Reaction SMILES: C([Mg]Cl)(C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O.[N:20]1[C:29]2[C:24](=[CH:25][C:26](C(OC)=O)=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.Cl>C(OCC)C.C1COCC1.O>[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[N:20]2)=[O:19]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Reactant: COC(=O)c1ccc2nccnc2c1
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc3nccnc3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2M solution of tert-butylmagnesium chloride (CAS Reg. No. 677-22-5) in diethyl ether (5.9 ml) was added to 2-chloro-4-methoxyphenylacetic acid (1.173 g, CAS Reg. No. 91367-09-8) in THF (10 ml). The mixture was stirred at room temperature for 30 min. A solution of methyl 6-quinoxalinecarboxylate (1 g, CAS Reg. No. 23088-23-5) in THF (3 ml) was added and the resulting mixture was stirred overnight. Aqueous HCl (25%, 1.5 ml) and water (30 ml) were added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2) to give the title compound (480 mg) as a light brown solid. MS (m/e)=313.2 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[Cl-].[Cl-].[O:47]=[C:48]1[NH:56][C:51]2=[NH+:52][CH:53]=[CH:54][CH:55]=[C:50]2[N:49]1[CH:57]1[CH2:62][CH2:61][NH2+:60][CH2:59][CH2:58]1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:60]2[CH2:61][CH2:62][CH:57]([N:49]3[C:50]4[C:51](=[N:52][CH:53]=[CH:54][CH:55]=4)[NH:56][C:48]3=[O:47])[CH2:58][CH2:59]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3CCOC3)cnc21
Reactant: O=c1[nH]c2[nH+]cccc2n1C1CC[NH2+]CC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3CCOC3)cnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
Triethylamine (43 μL, 0.310 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(tetrahydrofuran-3-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (42 mg, 0.103 mmol) and 4-nitrophenyl chloroformate (21 mg, 104 mmol) in tetrahydrofuran (3 mL) at 0° C. After 30 min, 2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (45 mg, 0.155 mmol), triethylamine (43 μL, 0.310 mmol) and dichloromethane (3 mL) were added and the mixture allowed to warm to ambient temperature. After 18 h, the reaction was concentrated. Purification by reverse phase HPLC (C-18, 90% water/acetonitrile→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (35 mg). MS 578.2702 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:27]#[N:28])[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
2-[(E)-2-(2,4-Difluorophenyl)vinyl]-5-[(3-bromophenyl)sulfonyl]pyridine (Example 27, 340 mg, 0.779 mmol) and zinc cyanide (110 mg, 0.93 mmol) were combined in N,N-dimethylformamide (5 mL) and degassed. Tetrakis-(triphenyl phosphine)palladium(0) (68 mg, 0.059 mmol) was added and the reaction heated at 100° C. under nitrogen for 6 hours. Further tetrakis(triphenylphosphine)palladium(0) (60 mg) was added and heating continued for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried over MgSO4 and concentrated in vacuo. The residue was purified by mass-triggered preparative HPLC (Nebula) to give the title compound as a beige solid (56 mg, 19%). This was purified further by recrystallisation from isopropyl alcohol/dichloromethane. δH (500 MHz, d6 DMSO): 9.16 (1H, s), 8.57 (1H, s), 8.40 (1H, dd, J=2.2, 8.4 Hz), 8.33 (1H, d, J=8.2 Hz), 8.18 (1H, d, J=7.8 Hz), 7.96–7.82 (3H, m), 7.76 (1H, d, J=8.3 Hz), 7.46 (1H, d, J=16.1 Hz), 7.36–7.31 (1H, m), 7.20–7.16 (1H, m); m/z (ES+) 383 [MH+].
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[C:13]([C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=O)=[N:14][O:15][C:11]=3[CH2:10][CH2:9][N:8]2C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl>C1COCC1>[C:1]1([CH:7]2[C:12]3[C:13]([CH2:16][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH2:10][CH2:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)N3CCCCC3)c2C1c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C2NCCc3onc(CN4CCCCC4)c32)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To solution of tert-butyl 4-phenyl-3-(piperidine-1-carbonyl)-6,7-dihydro-isoxazolo[4,5-c]pyridine-5(4H)-carboxylate (3.16 mmol, 1.0 eq.) in THF (6.5 ml) was added BH3-DMS (1.2 ml, 4.0 eq.) and the reaction mixture was heated at 110° C. for 6 h. The mixture was cooled to room temperature and MeOH (5 ml) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for overnight. 6N HCl (1.5 ml) was added and the mixture was again heated at 110° C. for 2 h. The reaction mixture was concentrated to dryness and the residue was dissolved in dichloromethane, and basified with saturated sodium carbonate solution. The organic layer was separated, dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography. Yield: 40%. [The regiochemistry was assigned by NMR experiments (COSY; HSQC, HMBC).]