Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[C:14]([CH3:15])=[CH:13][C:12]3[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=3[CH:6]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: C#CC(O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CC(=O)Oc1ccc(I)cc1
Product: CC(=O)Oc1ccc(C#CC(O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Yield: 24.6 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.28 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol with 1.44 g (5,5 mmol) of 4-iodophenyl acetate, 480 mg (25%) of the expected compound, with a melting point of 129°-130° C., were obtained.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[F:23][C:24]([F:31])([F:30])[C:25]1[NH:29][N:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:28]4[CH:27]=[CH:26][C:25]([C:24]([F:31])([F:30])[F:23])=[N:29]4)[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccn[nH]1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(N2CCC(n3ccc(C(F)(F)F)n3)C2=O)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 81 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.015 g, 0.041 mmol), 5-(trifluoromethyl)-1H-pyrazole (0.030 g, 0.22 mmol) and K2CO3 (0.030 g, 0.22 mmol) in DMF (0.5 mL) was stirred at 60° C. for 40 min. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.014 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=1.6 Hz, 1H), 7.57 (s, 1H), 7.38 (dd, J=8.8, 4.8 Hz, 2H), 7.18 (dd, J=8.4, 8.4 Hz, 2H), 6.58 (d, J=2.4 Hz, 1H), 5.07 (dd, J=8.8, 7.2 Hz, 1H), 4.03 (m, 1H), 3.82 (m, 1H), 2.97 (heptet, J=7.6 Hz, 1H), 2.84 (m, 2H), 1.20 (d, J=7.2 Hz, 3H), 1.12 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H19F4N5O [M+H]+ 422.1. found 422.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:39][CH2:40][C:41]([NH:43][C@H:44]([B:49]1[O:53][C@@H:52]2[CH2:54][C@@H:55]3[CH2:58][C@H:57]([C@:51]2([CH3:61])[O:50]1)[C:56]3([CH3:60])[CH3:59])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([B:49]1[O:53][C@@H:52]2[CH2:54][C@@H:55]3[CH2:58][C@H:57]([C@:51]2([CH3:61])[O:50]1)[C:56]3([CH3:59])[CH3:60])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:6]
Reactant: O=C(O)c1ccccc1Br
Reactant: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1ccccc1Br)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 2-bromobenzoic acid (0.124 g, 0.62 mmol) in DCM (2.25 mL) were added EDCI (0.119 g, 0.62 mmol), HOBt (0.084 g, 0.62 mmol), N-methyl morpholine (0.185 mL, 1.68 mmol) and 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide (0.2 g, 0.56 mmol). The reaction mixture was allowed to stir for 2 h and was concentrated. The residue was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-bromo-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.22 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)=[CH:14][CH:13]=2)[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[CH2:23](N)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:22]=[N:21][NH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:9][NH:10][CH2:11][CH3:23])=[CH:6][CH:7]=1
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reactant: CCN
Product: CCNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedures described in Examples 42A through to 42C but substituting methylamine for ethylamine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.11 [M+H]+ 326. 1H NMR (Me-d3-OD) δ 1.15 (3H, t), 2.83 (2H, q), 3.35-3.43 (2H, m), 4.25 (1H, t), 7.30-7.48 (6H, m), 7.57 (2H, d), 7.95 (2H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=O.Cl.[Cl:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][NH2:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][N:18]=[CH:3][C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: CC(C)(C)C=O
Reactant: NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)C=NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a mixture of 0.07 g of trimethylacetaldehyde and 5 ml of pyridine was added 0.30 g of O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.31 g (yield, 96.8%) of trimethylacetaldehyde O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-pentyl)oxime, nD23.0 1.5178.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[N:9]2)=[CH:4][CH:3]=1.[C:29](Cl)([Cl:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:29]([Cl:31])=[O:30])[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Product: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride was prepared from 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole (example 1) and phosgene in an analogous manner as described in example 6.
Reaction SMILES: [C:1]1([C:7]2[O:8]C3C(N=2)=NC=CC=3)C=CC=[CH:3][CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][C:25]2[C:26]([N:32]=1)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2.S(=O)(=O)(O)O.C(O)(=O)C>O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][C:25]2[C:26]([N:32]=1)=[N:27][C:28]([CH3:31])=[CH:29][C:30]=2[C:7](=[O:8])[CH2:1][CH2:2][CH3:3]
Reactant: c1ccc(-c2nc3ncccc3o2)cc1
Reactant: Cc1ccc2oc(-c3ccccc3F)nc2n1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCC(=O)c1cc(C)nc2nc(-c3ccccc3F)oc12

Procedure:
Using the procedure described in Example 1, but replacing -phenyloxazolo[4,5-b]pyridine by 2-(2-fluorophenyl)-5-methyloxazolo[4,5-b]pyridine and using 1.5 ml of sulfuric acid, 5 ml of acetic acid (and not 7.5 ml) and 5 ml of water (and not 7.5 ml), and on purification by chromatography on silica gel (40 to 63μ; 70-230 mesh; eluent: ethyl acetate/toluene, 2:8), the product of the title is obtained.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[C:12]([CH2:16][CH2:17][NH:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[C:24]=1[CH3:25])=[CH:11]2>ClCCl.ClCCl.CO>[F:5][C:6]1[C:14]2[N:13]([CH3:15])[C:12]3[CH2:16][CH2:17][N:18]([CH2:19][C:20]4[N:21]=[CH:22][N:23]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])[C:24]=4[CH3:25])[C:1](=[O:2])[C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1c(CNCCc2cc3cccc(F)c3n2C)ncn1S(=O)(=O)N(C)C
Solvent: ClCCl
Solvent: CO
Product: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of phosgene (12.5% v/v in toluene; 4 ml) in dichloromethane (4 ml) was added a solution of 4-[[[2-(7-fluoro-1-methyl-1H-indol-2-yl)ethyl]amino]methyl]-N,N,5-trimethyl-1H-imidazole-1-sulphonamide (100 mg) in dichloromethane (4 ml), and the resulting mixture was stirred for 1 h. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (5 ml). Aluminium chloride (68 mg) was added, and the mixture was heated at reflux for 3 h. The cooled mixture was then poured into 2M sodium hydroxide solution (80 ml) and extracted with dichloromethane (2×50 ml). The combined, dried organic extracts were evaporated in vacuo to leave a solid which was dissolved in dichloromethane:methanol (1:1; 50 ml) and adsorbed onto silica. Purification by FCC eluting with System A (200:8:1) gave a solid (21 mg) which was triturated with ether to give the title compound (14 mg), m.p. 162°-166°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.14 mmol), 4-chloro-3-nitrobenzaldehyde (0.50 mmol), methanol (1.5 mL), and acetic acid (0.070 mL) was added NaBH3CN (0.63 mmol) in methanol (1.3 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5/1 (6 mL), and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (44 mg, 53%): ESI/MS m/e 596.3 (M++H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[CH:35][C:34]=1[Pb+3]>C(Cl)(Cl)Cl.Cl>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[CH:37][C:38]=1[CH:6]1[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]1=[O:9]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Reactant: Clc1ccc(-c2ccc(Br)c([Pb+3])c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Temperature: 25 °C
Yield: 0.6 %

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (0.75 g, 4.9 mmol) and N,N-dimethylaminopyridine (2.52 g, 20.6 mmol) is added anhydrous chloroform (40 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (12 ml), followed by 4-bromo-4′-chlorobiphenyl-3-yllead triacetate (3.25 g, 5.1 mmol) in one portion and the reaction mixture is heated at 80° C. for 2 hours. The mixture is cooled to room temperature, diluted with chloroform (50 ml) and 1M aqueous hydrochloric acid (50 ml), and the mixture is stirred for 5 minutes. The precipitate is removed by filtration, the two phases separated, and the organic phase is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by flash column chromatography on silica gel, and fractions containing the desired compound are combined and evaporated to give a residue which is further purified by preparative reverse phase HPLC to give 4-(4-bromo-4′-chlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.013 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19](N)=O)[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C#CC2CC3(CCNC3)ON=2)C=CC=1.[O:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:45](Cl)=[O:46].CN=C=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:15][CH2:19][N:16]([C:45]([C:41]4[O:40][CH:44]=[CH:43][CH:42]=4)=[O:46])[CH2:17][CH2:18]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: O=C(Cl)c1ccco1
Agent: CN=C=O
Agent: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Product: O=C(c1ccco1)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 96, but replacing Compound 22c for Compound 27d and 2-furoyl chloride for methylisocyanate. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 8:2) giving 105 mg of the title compound. Yield: 60.2%.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C1COCC1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:16]=[C:15]([NH:25][S:26](=[O:38])(=[O:37])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:14]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47]>CN(C=O)C>[CH2:1]([O:4][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[N:16]=[C:15]([NH:25][S:26](=[O:37])(=[O:38])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:14]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCOc1nc(-c2ccncc2)nc(NS(=O)(=O)Nc2ccc(C(C)C)cc2)c1Oc1ccccc1OC
Temperature: 80 °C

Procedure:
To a mixture of allyl alcohol (1 ml) and THF (2 ml) was added sodium hydride (100 mg, 60% dispersion in mineral oil) followed by the addition of 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (100 mg, Referential Example 1e)). DMF (0.5 ml) was added and the reaction mixture was heated to 80° C. for 20 h. The solvents were evaporated, water (14 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by chromatography through silicagel with EtOAc/Hex=3:2 to give 4-i-propyl-phenyl sulfamic acid-[6-allyloxy-5-(o-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (10 mg). tR=5.36 min, (LC); [M+H]+=548.46 (ES+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[CH:7][C:6]=1[C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH3:4].C[Si]([C:19]#[N:20])(C)C.CN(C)C(Cl)=O>ClCCl>[CH2:1]([C:5]1[C:6]([C:12]([OH:14])=[O:13])=[CH:7][N:8]=[C:9]([C:19]#[N:20])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)C#N
Reactant: CCCCc1cc[n+]([O-])cc1C(=O)O
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CCCCc1cc(C#N)ncc1C(=O)O
Reaction time: 0.08 h

Procedure:
To a suspension of 4-n-butyl-3-carboxy-pyridine N-oxide (600 mg, 3 mmol) in 15 ml of dichloromethane is added trimethylsilylcyanide (595 mg, 6 mmol), and the solution is stirred for 5 min. Then dimethylcarbamoyl chloride (645 mg, 6 mmol) is added and stirring continued for 4 days under reflux. After cooling, the solution is evaporated to dryness under reduced pressure, and the residue is purified by column chromatography (dichloromethane/methanol 3:1) to yield 4-n-butyl-5-carboxy-2-cyano-pyridine, m.p. 267°-268°, Rf =0.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6].[CH2:19]1[CH2:21][CH2:20]1>>[CH:19]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)[C:5]#[N:6])[CH2:21][CH2:20]1
Reactant: C1CC1
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(Br)c1
Product: N#Cc1ccc(C2CCCc3cncn32)c(C2CC2)c1

Procedure:
3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile, prepared above, is converted to the corresponding cyclopropane by the method outlined in Tet. Lett. 2002, 43, 6987. MS (ESI) m/z 264.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 0.69-0.80 (m, 2H), 0.94-1.06 (m, 2H), 1.69-1.80 (m, 2H), 1.93-2.04 (m, 2H), 2.24-2.34 (m, 1H), 2.76-2.86 (m, 2H), 5.95 (d, J=6.1 Hz, 1H), 6.64-6.72 (m, 2H), 7.15 (s, 1H), 7.35 (s, 1H), 7.39 (d, J=8.1 Hz, 1H).
Reaction SMILES: C(C1OC2C(C(=O)CC3C=CC=CC=3)(C(=O)N2C(=C(C)C)C(OC)=O)N1)(O)=O.S(Cl)(Cl)=O.[N+](=[CH:35][C:36]([CH:38]1[O:44][CH:43]2[C:40]([C:54](=[O:62])[CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:41](=[O:53])[N:42]2[C:45](=[C:50]([CH3:52])[CH3:51])[C:46]([O:48][CH3:49])=[O:47])[NH:39]1)=[O:37])=[N-].[ClH:63]>C(Cl)Cl>[Cl:63][CH2:35][C:36]([CH:38]1[O:44][CH:43]2[C:40]([C:54](=[O:62])[CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:41](=[O:53])[N:42]2[C:45](=[C:50]([CH3:52])[CH3:51])[C:46]([O:48][CH3:49])=[O:47])[NH:39]1)=[O:37]
Reactant: Cl
Reactant: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)C=[N+]=[N-])OC12
Agent: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)CCl)OC12
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of 1.45 g of methyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 7 ml of methylene chloride is added 1.2 ml of thionyl chloride, and the mixture refluxed under heating for 2 hours and concentrated under reduced pressure. The resulting residue [methyl α-(3ξ-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate] is dissolved in 20 ml of tetrahydrofuran and mixed with 15 ml of ether solution of diazomethane which has been prepared from 1.5 g of nitrosomethylurea, and the mixture is kept at room temperature for 30 minutes. Into the resulting solution of methyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is introduced hydrogen chloride gas under ice-cooling until the spot of diazo ketone disappears. The mixture is concentrated under reduced pressure, and the residue is purified by chromatography on 17 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 1.19 g of methyl α-(3ξ-chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 75.3% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7].CCOCC.C(=O)(O)[O-].[Na+].[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([CH2:26][O:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>O>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7])=[O:29])=[CH:31][CH:32]=1)([O-:21])=[O:20]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCOCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)COCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.2 %

Procedure:
With cooling on an ice bath, to 596 mg of 2-(2-aminoethoxy)acetic acid dissolved in 10 ml of water was added an ether solution of 883 mg sodium bicarbonate and 1.29 g p-nitrobenzyloxycarbonyl chloride in dropwise manner. After stirring the reaction solution for 17 hours at room temperature, the resulting aqueous layer was collected, adjusted to acidic with concentrated hydrochloric acid and extracted with ethyl acetate, and the resulting organic layer was washed with water and dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure to yield 1.48 g of 2-(2-(p-nitrobenzyloxycarbonylamino)ethoxy)acetic acid.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)Nc2cccnc2)NC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.100 g, 0.35 mmol), 3-aminopyridine (0.036 g, 0.38 mmol), 1-hydroxybenzotriazole (0.047 g, 0.035 mmol), and 4-methylmorpholine (0.077 mL, 0.70 mmol) are dissolved in methylene chloride (2.5 mL), and the reaction is cooled to 0° C. To this solution is added N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.134 g, 0.70 mmol), and the reaction is allowed to warm up to room temperature and then stirred overnight. The reaction is partitioned between methylene chloride and water, the organic layer is dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (70% ethyl acetate/hexane) to give 3-{N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-amino}-pyridine, MS: M+1=364.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N:1]1([CH2:7][CH2:8][C:9]([Cl:15])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-piperidin-1-yl-propionic acid (472 mg, 3 mmol) in DCM (15 mL) at 0° C. was added oxalyl chloride (4.5 mmol) followed by one drop of DMF. After stirring for 2 hours at rt, the solvent was removed to give 3-piperidin-1-yl-propionyl chloride as a white solid. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (347 mg, 2.55 mmol) in DCM (10 mL) was added TEA (1 eq.) and 1-piperidinepropionic acid chloride. The mixture was stirred at rt for overnight. The reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 230 mg of 3-piperidin-1-yl-1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1-one as a light brown gel.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Cl:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1>>[Cl:7][C:8]1[N:13]=[C:12]([C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Clc1cccs1
Reactant: Clc1ncccn1
Product: Clc1nccc(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 2-chlorothiophene and 2-chloropyrimidine in a manner analogous to Example 249, Step 1. MS (M+H)+ 231.