Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.ClCCl.C(OCC)C>[ClH:24].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2F)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (891 mg) was dissolved in methanol (10 ml) and dichloromethane (5 ml), 2M HCl in diethyl ether (12.9 ml) was added and the reaction mixture was stirred at room temperature overnight, then cooled in ice bath, the resulted precipitate was filtered, washed with ether to yield 4-(2-fluoro-benzenesulfonyl)-piperazine hydrochloride salt (600 mg).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([CH2:32][CH3:33])[C:22](=[O:31])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]([CH3:34])=[CH:16][N:15]=2)[CH:7]=1)C.[Li+].[OH-]>>[CH2:32]([N:21]([CH2:20][C:19]1[C:14]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:35])=[O:3])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])=[N:15][CH:16]=[C:17]([CH3:34])[CH:18]=1)[C:22](=[O:31])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:33]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)CCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Product: CCN(Cc1cc(C)cnc1-c1cc(CC(=O)O)ccc1OC)C(=O)CCc1ccccc1

Procedure:
[3-(3-{[Ethyl-(3-phenyl-propionyl)-amino]-methyl}-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester was hydrolyzed with 1N aqueous LiOH to give the title compound.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[CH:8]=[C:9]([C:24]([F:27])([F:26])[F:25])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:12]2)[CH3:6].[OH:31][CH2:32][C:33]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C1CCCCC1>ClCCl>[C:46]1([C:33]2([CH2:32][O:31][CH:5]([C:7]3[CH:8]=[C:9]([C:24]([F:26])([F:27])[F:25])[CH:10]=[C:11]4[C:15]=3[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:13]=[CH:12]4)[CH3:6])[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (290 mg, 0.576 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (184 mg, 0.633 mmol) in dichloromethane (2 mL) at 0° C. was added cyclohexane (2 ml) and fluoroboric acid diethyl ether complex (0.016 ml, 0.115 mmol). The reaction was stirred at 0° C. for 45 min and was judged complete by TLC. The reaction was quenched with aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of ethyl acetate/hexanes from 12% to 100%. The product (173 mg, 0.273 mmol, 47.5% yield) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.77 (m, 1H), 7.39 (m, 1H), 7.14-7.29 (m, 5H), 7.07 (m, 1H), 6.54 (m, 1H), 5.15 (m, 1H), 3.32 (m, 2H), 3.21 (m, 2H), 3.00 m, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.45 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 0.75 (m, 2H), −0.09 (s, 9H); LC/MS (HPLC method 4): tR=4.36 min, 655.20(MNa)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH3:33])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>>[ClH:2].[CH2:34]([NH:36][C:37]([N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:29])=[CH:19][CH:18]=2)[CH:13]1[C:9]1([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][CH2:12]1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: CCCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Agent: Cl
Product: CCCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)N(C(=O)NCC)CC2
Yield: 23 %

Procedure:
The synthesis was performed according to example 33 (procedure 1), starting from butane-1-sulfonic acid (2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-amide hydrochloride (example 16) and ethyl isocyanate instead of 1-propyl isocyanate. The product was obtained as a white solid (16.0 mg, 0.03 mmol, 23%).
Reaction SMILES: [OH-].[Na+:2].C(O)C.[CH3:6][CH:7]([CH3:42])[CH2:8][C@H:9]([NH:31][C:32]([C@H:34]1[O:36][C@@H:35]1[C:37]([O:39]CC)=[O:38])=[O:33])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[CH2:14][CH2:13]1)=[O:11]>C(O)C>[CH3:6][CH:7]([CH3:42])[CH2:8][C@H:9]([NH:31][C:32]([C@H:34]1[O:36][C@@H:35]1[C:37]([O-:39])=[O:38])=[O:33])[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[CH2:16][CH2:17]1)=[O:11].[Na+:2]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(Cc2ccc(OC)c(OC)c2OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=O)[C@H](CC(C)C)NC(=O)[C@H]3O[C@@H]3C(=O)[O-])CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
Under cooling with ice, a 0.47N sodium hydroxide-ethanol solution (4.15 ml) was added to an ethanol solution (7.5 ml) of ethyl (2S,3S)-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]-oxirane-2-carboxylate (1.04 g), and the mixture was stirred at room temperature for 2.5 hours. After removal of ethanol by distillation under reduced pressure, water was added, and any insoluble matters were removed by filtration. The filtrate was concentrated and dried under reduced pressure to yield 1.00 g of sodium (2S,3S)-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]-oxirane-2-carboxylate as a light yellow powder (yield: 97%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][CH3:16])[CH2:10][CH2:9]1)(C)(C)C.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>C(Cl)Cl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:16][O:15][CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]1
Reactant: COC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H]1CC[C@H](N)CC1
Reaction time: 1 h

Procedure:
A solution of trans (4-methoxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (1.41 g, 5.80 mmol) in DCM (12 mL) was treated with trifluoroacetic acid (4 mL). The mixture was stirred for 1 hour then concentrated under vacuum. The residue was taken into ether and concentrated under vacuum a total of five times to afford 1.88 g of crude trans 4-methoxymethyl-cyclohexylamine trifluoroacetic acid salt as a colourless residue. This was not purified further. 1H NMR (400 MHz, CDCl3): δ 7.48 (br s, 3H), 3.34 (s, 3H), 3.22 (d, 2H), 3.15-3.00 (m, 1H), 2.11-2.00 (m, 2H), 1.94-1.83 (m, 2H), 1.65-1.50 (m, 1H), 1.46-1.31 (m, 2H), 1.13-0.96 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([NH2:23])=[N:20][C:19]=2[CH:24]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([NH:23][CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])=[N:20][C:19]=2[CH:24]=1
Reactant: Nc1nc2cc(Cl)ccc2s1
Reactant: CC1(C)Oc2ccncc2C2OC21
Product: CC1(C)Oc2ccncc2C(Nc2nc3cc(Cl)ccc3s2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 5-chloro-benzothiazol-2-ylamine as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[CH2:9]([OH:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[OH-].[Na+]>[CH2:9]([O:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCCCCCBr
Reactant: OCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#CCCCCCOCCc1ccccc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 104.3 %

Procedure:
6-Bromohexanenitrile (3.0 mL, 23 mmol) and tetrabutylammonium bromide (350 mg, 1.1 mmol) were dissolved in tetrahydrofuran (5 mL) and 50% aqueous sodium hydroxide (15 mL). Phenethyl alcohol (3.0 mL, 25 mmol) was added resulting in a precipitate. The mixture was heated to 65° C. whereupon the solid dissolved. The mixture was stirred at 65° C. for four hours then cooled to room temperature and left for 11 days. Water, hexanes and ethyl acetate were added and the mixture partitioned. The organics were washed with water, saturated sodium chloride, dried over sodium sulfate and evaporated to dryness to give the title intermediate (5.3 g, 24 mmol) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH2:16][N:15]([CH2:17][C:18]([NH2:20])=[O:19])[C:14](=[O:21])[CH:13]=1.[OH:22][CH2:23]C(CO)(CO)N.C[OH:31]>>[OH:22][CH2:23][N+:15]([CH2:14][OH:21])([CH2:16][OH:31])[CH3:17].[OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH2:16][N:15]([CH2:17][C:18]([NH2:20])=[O:19])[C:14](=[O:21])[CH:13]=1
Reactant: CO
Reactant: NC(CO)(CO)CO
Agent: NC(=O)CN1CC(C2=C(O)CN(CC(N)=O)C2=O)=CC1=O
Product: C[N+](CO)(CO)CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.0 g (0.010 mol) of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid diamide are suspended in 70 ml of methanol; 2.4 g of tris-(hydroxymethyl)-aminomethane are added and the whole is stirred at room temperature for 12 hours, during which time the free acid goes into solution and precipitates again in the form of a salt. The resulting precipitate is filtered off, washed with cold methanol and dried under greatly reduced pressure at 60°. The tris-(hydroxymethyl)-methylammonium salt of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid diamide is obtained in the form of white crystals having a melting point of 203° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4]([Cl:21])[N:3]=1>O1CCCC1.Cl>[ClH:21].[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:18][OH:17])[CH2:14][OH:15])=[C:4]([Cl:21])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2ncn(CCC(CO)CO)c2n1
Yield: 125.5 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.46 g, 1.5 mmol) in tetrahydrofuran (4.5 ml), hydrochloric acid (2.0M, 0.5 ml) was added. A white precipitate formed and after 0.5 hour the solution was diluted with further tetrahydrofuran and was filtered to give 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbut-1-yl) purine hydrochloride (290 mg, 63%), decomposed over 165° C.; λmax (H2O, pH5.5) 223 (ε 28,400), 245 (ε 4,620), and 307 (ε 7,620) nm; νmax (KBr) 3370, 3330, 3200, 2500, 1650, 1630, 1595, and 1505 cm−1; δH [(CD3)2SO] 1.53 (1H, m, CHCH2CH2), 1.83 (2H, q, J 7 Hz, CHCH2CH2), 3.35 (4H, d, J 6 Hz, 2×CH2O), 4.19 (2H, t, J 7 Hz, CH2N), 5.85 (9H, s, D2O exchangeable, 2×OH, NH2, HCl and H2O), and 8.57 (1H, s, 8-H). (Found: C, 39.04; H, 4.85; N. 22.36%; C10H14ClN5O4.HCl requires C, 38.98; H, 4.91; N, 22.73%).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].Cl>CCO>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]=[CH:3][CH:4]=[CH:5]3)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: NNc1ccc2ncccc2c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Yield: 51.3 %

Procedure:
A mixture of 1-(quinolin-6-yl)hydrazine hydrochloride (4.0 g, 20.5 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and cone. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield 3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (2.8 g, 51% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.84 (d, J=4.2 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.09 (s, 1H), 8.04 (s, 2H), 7.52 (m, 1H), 5.46 (s, 1H), 5.40 (brs, 2H), 1.29 (s, 9H). MS (ESI) m/z (M+H+): 267.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([NH2:9])=[N:7][N:8]=1.[CH3:10][C:11](=O)[CH2:12][CH3:13].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([NH:9][CH:11]([CH3:10])[CH2:12][CH3:13])=[N:7][N:8]=1
Reactant: CCC(C)=O
Reactant: COCc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)Nc1nnc(COC)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution (5 mL) of 5-(methoxymethyl)-4H-1,2,4-triazol-3-amine (0.3 g) and butan-2-one (0.25 mL) in acetic acid was added sodium cyanoborohydride (0.6 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.2 g, 45%).
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.[O:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:20][N:6]1[C:5]2[CH:21]=[CH:22][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:3][C:4]=2[C:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[N:9][CH2:8][C:7]1=[O:19]
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(I)ccc21
Reactant: OB(O)c1ccccc1Oc1ccccc1
Product: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(-c3ccccc3Oc3ccccc3)ccc21
Yield: 41 %

Procedure:
Prepared from 3-(7-iodo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 11 using the same conditions used to prepare Example 1 but using 2-phenoxy-phenyl boronic acid instead of benzene boronic acid. The title compound (90 mg) was obtained as a beige solid, in 41% yield.
Reaction SMILES: C[OH:2].[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[C:6](=O)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[BH4-].[Na+]>>[OH:2][CH:7]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:6][C:5]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:4]=1[Cl:3]
Reactant: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: OC(Cc1ccc(Cl)cc1Cl)n1ccnc1
Reaction time: 0.5 h

Procedure:
A 150 ml solution of methanol containing 15.6 g (0.061 mole) of 1-(2,4-dichlorophenacyl) imidazole cooled to 0°-5° C. was treated with 1.38 g (0.037 mole) of sodium borohydride in portions. The reaction was stirred 1/2 hour and the methanol removed at reflux while adding 100 ml of H2O. The refluxing aqueous mixture was treated with 16 ml of conc. HCl, cooled, and treated with 50 ml of conc. NH4OH. The mixture was extracted with methylene chloride, dried over MgSO4, and concentrated to give 11.3 g of a white solid product (66.8%), m.p. 139°-141° C. (from ethanol).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1([O:16][CH3:17])[CH2:15][C:7]2([CH2:10][C:9]([CH2:13][OH:14])([CH2:11][OH:12])[CH2:8]2)[CH2:6]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[CH2:18]([O:14][CH2:13][C:9]1([CH2:11][O:12][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][C:7]2([CH2:6][C:5]([O:4][CH3:3])([O:16][CH3:17])[CH2:15]2)[CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC1(OC)CC2(CC(CO)(CO)C2)C1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1(OC)CC2(CC(COCc3ccccc3)(COCc3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
Sodium hydride (755 mg, 17.3 mmol) was added to a dimethylformamide (40 ml)/tetrahydrofuran (20 ml) solution of the compound (1.56 g, 7.20 mmol) obtained in Step 1 above under ice cooling, the resulting mixture was stirred at room temperature for 10 minutes, then benzyl bromide (2.06 ml, 17.3 mmol) was added and the resulting mixture was stirred for 24 hours. Saturated ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=4:1 (v/v)] to give 2.25 g (79%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17]O.S(=O)(=O)(O)O>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:17])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 4-(4-hydroxyphenyl)benzoic acid (5 g), methanol (120 mL), and concentrated sulfuric acid (0.5 mL) was heated at 70° C. for 15 hours. The solution was cooled to ambient temperature, water (120 mL) was added, and the precipitated white solid was filtered. The filtered solid was washed with water and methanol and dried to yield 5.2 g (97%) of the methyl 4-(4-hydroxyphenyl)benzoate.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH:8]=[C:9]([CH3:14])[CH2:10][CH2:11][CH:12]=[O:13]>C(OCC)(=O)C.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]([CH3:14])[CH2:10][CH2:11][CH:12]=[O:13]
Reactant: CC(=CC1CC2CCC1C2)CCC=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CCC=O)CC1CC2CCC1C2
Yield: 65 %

Procedure:
5-(Bicyclo[2.2.1]heptan-2-yl)-4-methylpent-4-enal (20.6 g; 107 mmol) was hydrogenated in ethyl acetate (70 ml) in the presence of 5% palladium on charcoal (1.4 g) at room temperature and 30 bars. The product was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 9:1) followed by bulb-t-bulb distillation (100° C./0.25 mbar). The product was obtained as a 1:1 mixture of diastereoisomers in 65% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([O:37][CH3:38])([C:33]([F:36])([F:35])[F:34])[C:30](O)=[O:31]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30](=[O:31])[C:29]([F:28])([O:37][CH3:38])[C:33]([F:36])([F:35])[F:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: COC(F)(C(=O)O)C(F)(F)F
Product: COC(F)(C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1)C(F)(F)F

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and rac-2,3,3,3-tetrafluoro-2-methoxy-propionic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=437.1 [M+H]+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:17][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:9])=[O:8])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: COc1ccccc1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1COC(=O)[C@@H]1CSCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
0.200 g (0.6 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.138 g (1.0 mmol) of 2-methoxybenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:6) to obtain the product as a oil (0.19 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C[O:12][CH2:11][CH2:10]1.[Li+].CC([N-]C(C)C)C.C1OC1>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:10][CH2:11][OH:12])[N:3]=1
Reactant: C1CCOC1
Reactant: Cc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CO1
Solvent: O
Product: OCCCc1cccc(F)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.9 %

Procedure:
To a solution of 2-fluoro-6-methylpyridine (27 mmol) in 65 ml of freshly distilled THF was added via syringe 13.5 ml of 2M LDA, and the resulting mixture was stirred at -78° C. for 20 min. To the above cold solution was added 4 ml of 4M ethylene oxide and the mixture was allowed to warm to room temperature with stirring. The mixture was diluted with water, extracted with ether, and the organic layer was washed with water (2x) and brine, and dried over sodium sulfate. The organic solution was concentrated, and the residue was purified by flash chromatography (chloroform/ethanol, 10:1) to yield 1.3 g (30.9%) of 2-fluoro-6-(3-hydroxypropyl)pyridine, as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20](F)[CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:22]2[CH:23]=[C:18]([Br:17])[CH:19]=[CH:20][C:21]=2[N+:24]([O-:26])=[O:25])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC1CCCN(c2cc(Br)ccc2[N+](=O)[O-])C1
Temperature: 25 °C

Procedure:
A solution of (2-Piperidin-3-yl-ethyl)-carbamic acid tert-butyl ester (0.087 mmol, 0.020 g) and 4-Bromo-2-fluoronitrobenzene (1.0 eq, 0.019 g), N,N-diisopropylethylamine (1.2 eq, 13.5 μL) in ACN (2 mL) was irradiated using microwave for 18 minutes at a temperature of 130° C. The solution was then cooled to room temperature and concentrated in vacuo to provide {2-[1-(5-Bromo-2-nitro-phenyl)-piperidin-3-yl]-ethyl}-carbamic acid tert-butyl ester. HPLC-MS RT=2.37 min, mass calculated for formula C18H26BrN3O4 427.11, observed LCMS m/z 428.22 and 430.11 (M+H).