Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]C1C=C(OC)C=CC=1.[Mg:10].[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)C(=O)C[CH2:12]1.Cl>O1CCCC1.O>[CH3:12][O:11][C:20]1[CH:15]=[C:16]([Mg:10][Br:1])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCOc2ccccc21
Reactant: [Mg]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc([Mg]Br)c1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of 3-methoxyphenyl magnesium bromide was prepared by adding 27.7 g of m-bromoanisole to a suspension of magnesium turnings (3.6 g) in 150 ml of tetrahydrofuran (THF) dropwise over 1 hr. The mixture was heated at reflux for 2 hrs. The resulting solution was cooled to 5° C. and a solution of 4-chromanone (20.0 g) in 50 ml of dry THF added over 2 hrs. at 15° C. The resulting mixture was stirred overnight at room temperature, cooled to 10° C., and treated with 1N HCl until pH 7 was reached. The mixture was diluted with water, extracted twice with 500 ml of ether, and the combined extracts dried over MgSO4. Filtration and evaporation gave 29.6 g of the title compound as an oil. NMR (CDCl3); δ3.81 (S,3H), 4.80 (d,J=4 Hz, 2H) 5.76 (t,J=4 Hz, 1H), 6.7- 7.4 (M,8H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>O.C(OCC)(=O)C>[CH:13]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])=[CH:20][CH:21]=1)([CH3:15])[CH3:14]
Reactant: CCCc1nc(C)n(-c2ccc(C(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(C(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.82 g), sodium hydrogen carbonate (2.64 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-isopropylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.21 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.51 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with 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 to give the title compound as colorless crystals (0.90 g, 66%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1>O>[Cl:1][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(C)ccn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(Cl)cn1
Reaction time: 18 h
Yield: 83 %

Procedure:
9.2 g (69 mmol) of N-chlorosuccinimide was charged to a N,N-dimethylformamide (DMF) 15 ml solution of 8.0 g (65 mmol) of 2-methoxy-4-methylpyridine, followed by stirring for 18 hours. Water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 8.5 g (yield: 82%) of 5-chloro-2-methoxy-4-methylpyridine (melting point 32 to 33° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:8][C:9]([C:11]2[N:15]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH:14]=[CH:13][N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1c(Br)cccc1NC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(Cn1ccnc1C(=O)Nc1cccc(Br)c1C)OCC
Temperature: 100 °C
Yield: 81.8 %

Procedure:
Step 2 A solution of N-(3-bromo-2-methylphenyl)-1H-imidazole-2-carboxamide (0.70 g, 2.499 mmol) in DMF (12.5 mL) was treated with potassium carbonate (0.794 g, 5.75 mmol) and 2-bromo-1,1-diethoxyethane (0.395 mL, 2.62 mmol). The suspension was heated at 100° C. overnight. The mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 85:15 to 20:80 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-1-(2,2-diethoxyethyl)-1H-imidazole-2-carboxamide as a white solid (0.81 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 10.17 (1H, s), 7.51 (1H, d, J=2.6 Hz), 7.49 (1H, d, J=2.6 Hz), 7.44 (1H, d, J=1.1 Hz), 7.18 (1H, t, J=8.0 Hz), 7.10 (1H, d, J=1.1 Hz), 4.75 (1H, t, J=5.4 Hz), 4.52 (2H, d, J=5.3 Hz), 3.63 (2H, dq, J=9.7, 7.0 Hz), 3.35-3.44 (2H, m), 2.31 (3H, s), 1.05 (6H, t, J=7.0 Hz). Mass spectrum m/z 396, 398 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]4[CH2:20][O:19]4)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:19])[CH2:20][N:24]4[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]4)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1c2cc(C3CO3)ccc2ccc2ncc(Cl)cc12
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc3ccc4ncc(Cl)cc4c(=O)c3c2)CC1

Procedure:
3-chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (60 mg, 0.21 mmol) was suspended in 2.5 mL of methanol. tert-Butyl piperazine-1-carboxylate (98 mg, 0.53 mmol) was added and the reaction was heated to reflux for 8 hours. The resulting mixture was concentrated in vacuo and purified directly via flash chromatography (15-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 9.79 (d, 1H); 8.49 (d, 1H); 8.22 (d, 1H); 7.77 (dd, 1H); 7.60 (d, 1H); 7.31 (d, 1H); 7.25 (d, 1H); 4.91 (dd, 1H); 3.50-3.45 (m, 4H); 2.72 (broad s, 2H); 2.63 (dd, 1H); 2.50 (dd, 1H); 2.44 (broad s, 2H); 1.46 (s, 9H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for (C25H29ClN3O4) [M+H]+, 470.2; found 470.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12][N:11]=[C:10]([C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[S:16][CH:17]=2)[CH2:9]1.[ClH:31]>ClCCl.O1CCOCC1>[Cl-:31].[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12][N:11]=[C:10]([C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][NH2+:21][CH2:20][CH2:19]3)[S:16][CH:17]=2)[CH2:9]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Product: [Cl-]
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.70 g) in dichloromethane was added dropwise, at 0° C., a 4 molar solution of hydrogen chloride (4.0 eq.) in 1,4-dioxane. The reaction mixture was stirred at 0° C. and then gradually warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride were removed. This gave 4-{4-[5-(2-hydroxy-phenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidinium chloride (1.45 g).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][OH:22])[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: OCCNCCO
Product: O=C(c1ccccc1)c1ccc(N(CCO)CCO)cc1
Temperature: 155 °C
Yield: 91.1 %

Procedure:
A 2000 mL two-neck flask was charged with 4-fluorobenzophenone (200.0 g; 1.00 mol) and diethanolamine (735.2 g; 7.00 mol). The flask was flushed with nitrogen, fitted with a reflux condenser and heated to 155° C. for 48 h under a gentle stream of nitrogen. Complete conversion of the starting 4-fluorobenzophenone was confirmed by TLC. After cooling to ambient temperature, the dark viscous reaction mass was diluted with ethyl acetate (2500 mL) and extracted with water (2000 mL). The organic phase was dried (MgSO4), filtered and evaporated to give {4-[bis(2-hydroxyethyl)amino]phenyl}(phenyl)methanone (bright yellow powder; 260 g; 91% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][C:29]#[C:30][CH2:31][OH:32])[N:15]=[C:14]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH:39]1([N:45]=[C:46]=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[N:13]=[C:14]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[N:15]=[C:16]([O:27][CH2:28][C:29]#[C:30][CH2:31][O:32][C:46](=[O:47])[NH:45][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:17]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCC#CCO
Reactant: O=C=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCC#CCOC(=O)NC1CCCCC1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Under argon, a suspension of 50 mg of 5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 3), 10 mg of DMAP and 25 μl of cyclohexylisocyanate in 4 ml of chloroform and 3 ml of DMF was stirred for 72 h at 70° C. The mixture was diluted with 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and 2×25 mlf of water. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with a gradient of hexane:ethyl acetate 1:1 to ethyl acetate, then with DCM containing 4% of methanol to give 38 mg of cyclohexylcarbamic acid 4-[6-(5-methylpyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a beige foam. LC-MS: tR=4.89 min, [M+1]+=659.33, [M−1]−=657.25.
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@:15]4([CH3:25])[C@@:19](O)([C:20]([CH2:22]O)=[O:21])[CH2:18]C[C@H]4[C@@H]3CCC1=CC(=O)CC2.C[C@@]12[C@@](O)([C:37](CO)=[O:38])CC[C@H]1[C@@H]1CCC3[C@@](C)([C@H]1[C@@H](O)C2)C=CC(=O)C=3.C(OC[C@@H](O)[C@]1(O)[C@]2(C)[C@H]([C@H]3[C@H]([C@@H](O)C2)[C@]2(C)C(=CC(=O)C=C2)CC3)CC1)(=[O:55])C.Cl(O)(=O)(=O)=O>>[C:20]([CH:19]([CH2:15][CH3:25])[C:18]([O:38][CH3:37])=[O:55])(=[O:21])[CH3:22]
Reactant: CC(=O)OC[C@@H](O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCC(C(C)=O)C(=O)OC

Procedure:
Hydrocortisone or prednisolone with 20-hydroxy and 21-acetoxy groups are known, e.g., (I) (20R)-21-acetoxy-11β, 17,20-trihydroxy-3-oxo-1,4-pregnadiene; and (I) is reacted with an alkyl acetylalkanoate in the presence of perchloric acid to produce the corresponding 17,20-carboxycyclic acetal pregnane derivatives, e.g., when methyl acetylbutyrate is used the product is (II) (20R)-21-acetoxy-11β-hydroxy-3-oxo-17,20-(methyl,methoxycarbonyl-n-propyl)methylenedioxy-1,4-pregnadiene;
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH:21]3[OH:29])[CH:13]=2)[N:6]=1)=[O:4].[NH2:30][C@H:31]1[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]1>O>[NH2:11][C:10]1[C:5]([C:3]([NH:30][C@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)=[O:4])=[N:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][C@@H:21]3[OH:29])[CH:13]=2)=[CH:8][N:9]=1
Reactant: COC(=O)c1nc(-c2cccc(CNC3c4ccccc4CC3O)c2)cnc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: O
Product: Nc1ncc(-c2cccc(CN[C@@H]3c4ccccc4C[C@@H]3O)c2)nc1C(=O)N[C@H]1CCCNC1
Temperature: 120 °C
Yield: 58.7 %

Procedure:
A mixture of 3-amino-6-{3-[(2-hydroxy-indan-1-ylamino)-methyl]-phenyl}-pyrazine-2-carboxylic acid methyl ester (400.0 mg, 1.02 mmol) and 1,1-dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (970.0 mg, 4.84 mmol) was heated to 120° C. overnight. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (2×50 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by column chromatography (3% MeOH/Dichloromethane) and subsequently it was treated with 4.0 M HCl in dioxane (20 mL) to give 3-amino-6-[3-({[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}methyl)phenyl]-N-[(3S)-piperidin-3-yl]pyrazine-2-carboxamide, 275.0 mg (58.7% yield). 1H NMR (400 MHz, d4-MeOH): δ 8.72 (s, 2H), 8.18 (s, 1H), 7.80 (d, 1H), 7.60 (m, 2H), 7.38 (m, 3H), 4.80 (s, 1H), 4.50(s, 2H), 4.40 (m, 1H), 3.65 (m, 2H), 3.42 (m, 5H), 3.16 (m, 2H), 2.15 (m, 2H), 1.87 (m, 1H); MS (EI) for C26H30N6O2: 459.31 (MH+).
Reaction SMILES: [NH2:1][OH:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]#[N:14])[C:8]([C:15]1[C:19]([CH3:20])=[CH:18][S:17][C:16]=1[CH3:21])=[C:7]2[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(Cl)Cl.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13](=[N:1][OH:2])[NH2:14])[C:8]([C:15]1[C:19]([CH3:20])=[CH:18][S:17][C:16]=1[CH3:21])=[C:7]2[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: NO
Reactant: Cc1csc(C)c1-c1c(-c2ccc(O)cc2)c2cc(Cl)ccc2n1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2)c2cc(Cl)ccc2n1C(N)=NO
Temperature: 0 °C
Reaction time: 65 h
Yield: 15.4 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.69 mL, 11.0 mmol) was added to 5-chloro-2-(2,4-dimethylthiophen-3-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile (42 mg, 0.11 mmol) in DCM (5 mL) at 0° C. and the reaction was stirred at 0° C. for 65 h. Brine was added and the aqueous mixture was extracted with DCM. The solvent was concentrated and the crude product was purified by preparative HPLC to give 5-chloro-2-(2,4-dimethylthiophen-3-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1H-indole-1-carboximidamide (7.0 mg, 35%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 414.5; 412.4 (M+H), 412.3; 409.9 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.65 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.25 (dd, 1H, J=8.8, 2.1 Hz), 7.10 (m, 2H), 6.83-6.80 (m, 3H), 2.18 (s, 3H) and 1.95 (d, 3H, J=1.1 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][N:14]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]=2[C:27]=1[Cl:28])=[O:6].[C:29]([O-:32])(=[O:31])[CH3:30].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:29]([O:32][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][N:14]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]=2[C:27]=1[Cl:28])=[O:6])(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(NC(=O)NCCCl)c2Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 25 °C
Reaction time: 120 h

Procedure:
3.7 g of 1-(2-chloroethyl)-3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea dissolved in 100 ml of acetonitrile are treated with 1.83 g of potassium acetate and 4.21 g of 18-crown-6. The mixture is then stirred at room temperature for 5 days, concentrated, treated with water/methylene chloride and the aqueous solution is extracted several times with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 350 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethanol/ether. There is obtained 2-[3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10]CCCC.[C:16]([Li])([CH3:19])([CH3:18])[CH3:17].[B:21](OC)([O:24]C)[O:22]C.[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[C:16]([O:10][C:9]([NH:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[B:21]([OH:24])[OH:22])=[O:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCCOC(=O)Nc1ccccc1F
Reactant: [Li]C(C)(C)C
Reactant: COB(OC)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1B(O)O
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of Cert-butyl 2-fluorophenylcarbamate (from step 1) (1.0 eq.) in tetrahydrofuran (0.25 M) at −78° C. under N2 atmosphere was added dropwise 1.7 M tert-butyllithium (2.4 eq.). The reaction was warmed to −40° C. slowly over 2 hours, and neat trimethyl borate (3.8 eq.) was added. The reaction was warmed to room temperature over 30 minutes. An aqueous solution of 1N NaOH was slowly added to the reaction and stirred for 15 minutes. The mixture was poured into ethyl acetate and acidified with 3N HCl to dissolve the solids. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The resulting solids were stirred in 1:1 ether/hexane, filtered, and dried. The solids were carried onto the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=[C:13]([O:1][CH2:2][CH2:3][C:4]3[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=3)[C:7]#[N:8])[CH:23]=[C:17]12
Reactant: N#Cc1cccc(CCO)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1cccc(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from of 3-(2-hydroxyethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1.C[C@H](N)C1C=CC=CC=1.CCCCCCC>COC(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@H:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Agent: C[C@H](N)c1ccccc1
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Product: O=C(O)C1=Cc2cc(Cl)ccc2O[C@@H]1C(F)(F)F
Reaction time: 24 h
Yield: 45.8 %

Procedure:
To a solution of 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 1, Step 2)(12.00 g, 43.07 mmol) and (S)(-)-α-methylbenzylamine (2.61 g, 21.54 mmol) in methyl-tert-butyl ether (30 mL) was slowly added n-heptane (200 mL) until the mixture became cloudy. The mixture was heated (steam bath) to boiling and set aside for 24 h during which time crystals formed. Filtration of the suspension yielded a crystalline product (5.5 g) which was recrystallized from methyl-tert-butyl ether (30 mL) and n-heptane (200 mL) yielding upon filtration a white solid (3.1 g). This solid was dissolved in EtOAc (100 mL) and washed with 1 N hydrochloric acid (50 mL) and brine (2×50 mL), dried over MgSO4 and concentrated in vacuo yielding a white solid. Recrystallization of this solid from methyl-t-butyl ether/n-heptane yielded the title compound as the highly enriched isomer, a white solid (2.7 g, 45%): mp 126.7-128.9° C. 1H NMR (CDCl3 /300 MHz) 7.78 (s, 1H), 7.3-7.1 (m, 3H), 6.94 (d, 1H, J=8.7 Hz), 5.66 (q, 1H, J=6.9 Hz). Anal. Calc'd for C11H6O3F3Cl: C, 47.42; H. 2.17; N, 0.0. Found: C, 47.53; H, 2.14; N, 0.0. This compound was determined to have an optical purity of greater than 90% ee.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[C:10]([OH:12])=[O:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C(O)C1NCC2CCCCC21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC3CCCCC3C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
Octahydroisoindole-1-carboxylic acid (0.125 g; 0.74 mmol) from Example 1, Step A, p-toluenesulfonyl chloride (0.155 g; 0.814 mmol), and sodium carbonate (0.157 g; 1.48 mmol) were dissolved in water (3 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and washed with EtOAc. The water layer was acidified with concentrated. HCl and extracted with CH2Cl2 (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford N-(4-methylbenzenesulfonyl)-octahydroisoindole-1-carboxylic acid (0.15 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:28])([F:27])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[CH2:24]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:24][C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:28])=[CH:21][CH:20]=2)=[O:26])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-trifluoromethoxyphenyl)-2-chloroacetamide (51 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced the residue was purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.35 (d, J=6 Hz, 2H), 7.55 (t, J=6 Hz, 1H), 7.76 (m, 2H), 8.12 (d, J=5 Hz, 1H), 9.98 (s, 1H); MS (ESI/APCI+) m/e 381 (M+H)+.