Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([CH3:16])=[CH:12][N:11]([C@H:17]2[CH2:21][CH2:20][C@H:19]([O:22][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:18]2[CH2:40][O:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]1=[O:61])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.O>[C:1]([N:9]1[C:14](=[O:15])[C:13]([CH3:16])=[CH:12][N:11]([C@H:17]2[CH2:21][CH2:20][C@H:19]([OH:22])[C@H:18]2[CH2:40][OH:41])[C:10]1=[O:61])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@H]2CC[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)n(C(=O)c2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cn([C@H]2CC[C@H](O)[C@H]2CO)c(=O)n(C(=O)c2ccccc2)c1=O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Compound 56 (0.45 g, 0.55 mmol) was dissolved in mixture of TFA (15 ml) and water (5 ml). The solution was stirred under argon for 1 h, then concentrated, co-evaporated 2 times with water to remove residual TFA and chromatographed on silica eluting with a gradient (5-7%) of MeOH in dichloromethane to yield nucleoside 57 (0.140 g, 75% yield) as a white solid. 1H NMR (DMSO-d6): δ7.95-7.92 (m, 2H), 7.80-7.74 (m, 2H), 7.57 (t, J=7.7 Hz, 2H), 4.96-4.86 (m, 1H), 4.81 (d, J=5.1 Hz, 1H), 4.62 (t, J=4.0, 1H), 3.95-3.88 (m, 1H), 3.50-3.45 (m, 1H), 3.35-3.25 (m, 1H), 2.12-1.98 (m, 4H), 1.86 (s, 3H), 1.48-1.38 (m, 1H).
Reaction SMILES: C(Cl)Cl.[S:4]([NH:14][C@H:15]([C:22]([OH:24])=O)[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].Cl.[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(N(CC)CC)C>[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:22](=[O:24])[C@H:15]([CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[NH:14][S:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1)(=[O:5])=[O:6])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 ml of desiccated methylene chloride were added 10 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidine (47) and 6.50 g of L-proline benzyl ester hydrochloride and the mixture was cooled in an ice bath. After adding thereto 2.72 g of triethylamine, 6.05 g of DCC was further added to the mixture and the resultant mixture was stirred for 30 minutes in an ice-bath and stirred overnight at room temperature. Insoluble matters were filtered off and the filtrate was concentrated. The residue thus formed was purified by silica gel column chromatography. By eluting the product with ethyl acetate-benzene (1:1), 13.5 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidyl-L-proline benzyl ester (49) was obtained.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:13])[C@H:8]2[CH2:9][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:10][CH2:11]Cl.Cl.[CH2:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[CH3:2][C:3]1([CH3:13])[C@H:8]2[CH2:9][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:10][CH2:11][O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][OH:21]
Reactant: OCCCCCO
Reactant: CC1(C)[C@H]2CC[C@@H](CCCl)[C@@H]1C2
Agent: Cl
Agent: [Na]
Product: CC1(C)[C@H]2CC[C@@H](CCOCCCCCO)[C@@H]1C2
Temperature: 130 °C

Procedure:
Over the course of 12 hours, 12.2 g of elemental sodium were dissolved in portions in 357 ml of 1,5-pentanediol at a temperature of 90° C. 80 g of 2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-y l)ethyl chloride were then added dropwise to this solution, and the reaction mixture was heated at 130° C. for 15 hours. The reaction mixture was worked up by cooling to room temperature, adding 300 ml of a 5% strength aqueous hydrochloric acid solution, and extracting the mixture with ether. After concentrating the ether extract, 99.6 g of crude 5-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl )ethoxy]pentanol were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:17]C(=O)C)[CH:5]=[CH:6][C:7]=1[C:8]([CH3:16])([CH3:15])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].Cl.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:14][O:13][CH2:12][CH2:11][O:10][CH2:9][C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH2:17])=[CH:3][C:2]=1[OH:1])([CH3:16])[CH3:15]
Reactant: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COCCOCC(C)(C)c1ccc(N)cc1O
Yield: 7.3 %

Procedure:
A mixture of N-{3-hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (1 g, 3.5 mmol) and HCl (5 mL) was heated at reflux for 1 h. The mixture was basified with Na2CO3 solution to pH 9 and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to obtain 2-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol (C-25) (61 mg, 6%). 1HNMR (CDCl3) δ 9.11 (br s, 1H), 6.96-6.98 (d, J=8 Hz, 1H), 6.26-6.27 (d, J=4 Hz, 1H), 6.17-6.19 (m, 1H), 3.68-3.69 (m, 2H), 3.56-3.59 (m, 4H), 3.39 (s, 3H), 1.37 (s, 6H); ESI-MS 239.9 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(O)(=O)C.[C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH3:15]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:14]([CH3:15])=[C:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: COc1ccccc1N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=C(C)Nc1ccccc1OC

Procedure:
A mixture of 2-methoxyaniline (10 g), acetic acid (1 ml) and ethyl 2-acetylpropionate (12.3 g) in benzene (30 ml) was refluxed for 24 hours, and then the solvent was removed to give crude ethyl 3-(2-methoxyanilino)-2-methyl-2-butenoate, which was used as a starting compound at the following example without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([OH:9])[CH:8]=1)[CH3:2].[CH:11](OCC)(OCC)[O:12]CC.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[C:4]=1[CH:11]=[O:12])[CH3:2]
Reactant: CCc1cc(O)cc(O)c1
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCc1cc(O)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
To a suspension of 5-ethyl-benzene-1,3-diol (2.17 g, 15.72 mmol) and triethyl orthoformate (23.26 g, 157 mmol) in benzene (40 mL) was added AlCl3 (6.30 g, 47.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. After cooling to room temperature, the mixture was poured onto ice and acidified with HCl. The mixture was extracted with EtOAc and the organic extracts was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2-ethyl-4,6-dihydroxy-benzaldehyde (1.0 g, 38%). 1H NMR (400 MHz, CDCl3δ 12.40 (s, 1H), 10.08 (s, 1H), 6.25 (s, 1H), 6.00 (s, 1H), 5.80 (s, 1H), 2.90 (m, 2H), 1.30 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:22][C:14]1[NH:15][C:16]3[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5](=[O:11])[NH:6]2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-methyl-2-oxindole (147 mg), 3-methyl-indole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 4-methyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5][CH:4]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:3]1.[CH:23]1([N:26]2[C:35]3[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=3[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]2)[CH2:25][CH2:24]1>>[C:20]([NH:19][CH2:18][CH:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][N:12]([C:33]4[C:34]([F:36])=[C:35]5[C:30]([C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27][N:26]5[CH:23]5[CH2:25][CH2:24]5)=[CH:31][C:32]=4[F:38])[CH2:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NCC1CN(c2ccc3c(c2)CCCNC3)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CC(=O)NCC1CN(c2ccc3c(c2)CCCN(c2c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c2F)C3)C(=O)O1

Procedure:
The title compound was prepared in a procedure analogous to that used in Example 6, using N-[2-Oxo-3-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)-oxazolidin-5-ylmethyl]-acetamide (0.25 g) and 1-Cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.23 g). The product was triturated with EtOH to purify. MS (APCI)AP+, 567. NMR (DMSO6)1.1-1.22 (m, 4H), 1.78 (s, 3H), 1.87 (brm, 2H), 3.0 (brs, 2H), 3.38 (t, 2H), 3.7 (m, 3H), 4.04 (t, 2H), 4.43 (s, 2H), 4.61 (m, 1H), 7.13 (d, 1H), 7.26 (d, 1H), 7.35 (s, 1H), 7.78 (d, 1H), 8.2 (t, 1H), 8.61 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([NH:19][C:4](=[O:6])[C:3]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:2]=1[OH:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCN
Reactant: COC(=O)c1cc(O)ccc1O
Product: CCCCCCNC(=O)c1cc(O)ccc1O
Temperature: 60 °C

Procedure:
Methyl 2,5-dihydroxybenzoate (1 g) is dissolved in 10 mL of n-hexylamine. After overnight heating in an oil bath (60° C.), the mixture is cooled to room temperature. n-Hexylamine is removed under reduced pressure. The residue is dissolved in ethyl acetate and further extracted with 1 N HCl. The organic layer is extracted with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. Solvent is removed under reduced pressure to yield the product as an off-white powder.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:25])[C:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:29]>C(Cl)(Cl)Cl>[ClH:29].[ClH:1].[ClH:29].[NH2:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][C:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)([N:3]([CH3:25])[CH3:2])[CH2:5][CH2:6]1
Reactant: ClC(Cl)Cl
Reactant: CN(C)C1(c2cccs2)CCN(CCNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CN(C)C1(c2cccs2)CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
HCl gas was passed through a solution of 9 g (1 eq.) tert-butyl 2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethylcarbamate in chloroform at 0° C. for ˜30 min. The reaction mixture was then stirred at room temperature for one hour. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure and 9 g (97%) of product were obtained in the form of a white solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>>[CH:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:10]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:16][CH:15]=1)([CH3:13])[CH3:12]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CC(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1ccc(CN(Cc2ccc(C(C)C)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-isopropylbenzylbromide (469 mg; 0.376 ml; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.147 g (36.9%); MS m/z: 398.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.16 (d, 12H, 3J=7.0 Hz); 2.83 (hept, 2H, 3J=7.0 Hz); 4.62 (s, 4H); 6.69 (br s, 1H); 6.73 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 7.16-7.20 (m, 8H); 7.32 (d, 1H, 3J=8.9 Hz); 7.89 (s, 1H); 11.90 (br s, 1H); HPLC (METHOD [A]): rt 19.95 min (94.4%)
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:16]=[C:15]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][C:27]=3[F:38])[CH:14]=2)=[CH:11][CH:12]=1)=O)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[N:34]1([C:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][C:15]3[CH:14]=[C:13]([C:10]4[NH:9][C:8]([C:6]5[O:3][C:1]([CH3:2])=[N:4][N:5]=5)=[CH:12][CH:11]=4)[CH:18]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:16]=3)=[C:27]([F:38])[CH:28]=2)=[O:33])[CH2:35][CH2:36][CH2:37]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NNC(C)=O)[nH]2)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(-c3nnc(C)o3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
N′-Acetyl-5-{3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carbohydrazide (86 mg, 0.16 mmol) synthesized in Example (66h) was dissolved in dichloromethane (5 mL), and triethylamine (0.1 mL, 0.72 mmol) and p-toluenesulfonic acid chloride (69 mg, 0.36 mmol) were added, followed by stirring at room temperature overnight. The reaction solution was diluted with dichloromethane (60 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-100%) to afford the desired product (57 mg, yield 69%) as a white solid.
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>CN(C=O)C.O.O.[Cu](Cl)Cl>[Cl:1][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:11]=1
Reactant: [Cl-]
Reactant: Oc1ccccc1OC(F)(F)F
Agent: Cl[Cu]Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(Cl)cc1OC(F)(F)F
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A solution of copper(II)chloride dihydrate (37.2 mmol, 6.34 g) and lithium chloride (18.6 mmol, 788 mg) in DMF (60 mL) was heated to 80° C. before the addition of 2-(trifluoromethoxy)phenol (18.6 mmol, 4 g) dropwise. The reaction was stirred at 100° C. for 72 hours. After cooling, the reaction mixture was partitioned between EtOAc (60 mL) and water (120 mL), extracted with EtOAc (60 mL). The organic layer was washed with water (60 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting product with a gradient of 0-100% DCM in heptane to yield the title compound as a waxy solid (637 mg, 10%). This was used in the next step with no further purification.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[CH2:8][O:7][CH2:6][C:5]=12.C([Sn](=O)CCCC)CCC.C[Si]([N:32]=[N+:33]=[N-:34])(C)C>C1(C)C=CC=CC=1>[NH:32]1[C:14]([C:13]2[CH:16]=[CH:17][C:10]([CH:9]3[CH2:8][O:7][CH2:6][C:5]4=[CH:1][N:2]=[CH:3][N:4]34)=[CH:11][CH:12]=2)=[N:15][N:34]=[N:33]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(C2COCc3cncn32)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: c1cc(C2COCc3cncn32)ccc1-c1nnn[nH]1
Temperature: 125 °C

Procedure:
A solution of 0.17 mmol of 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile (Example 1) and 0.017 nimbi of dibutyltin oxide in 4.6 ml of toluene is mixed with 3.34 mmol of trimethylsilyl azide. The reaction mixture is heated at 125° C. overnight. It is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:14]=[C:13]1[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:15])[N:1]1[C@H:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CSCC[C@@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSCC[C@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 93.2 %

Procedure:
A solution of (R)-2-amino-4-(methylthio)butanoic acid (50 g, 335 mmol), finely ground phthalic anhydride (49.6 g, 335 mmol) and triethlamine (4.67 ml, 33.5 mmol) in toluene (450 ml) was stirred and heated under vigorous reflux in a Dean-Stark apparatus for 2.5 h. Volatiles were evaporated and to the residue was added 600 ml water and 6 ml hydrochloric acid and the mixture stirred vigorously with a mechanical stirrer. After stirring for 30 minutes, the suspension was filtered and filtrate evaporated under vacuum to give the title compound (87.24 g=92% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(OCC)(=O)C>[CH2:33]([O:20][C:19](=[O:21])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A solution of 30 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 400 ml of ethyl acetate was treated with 9.63 g of triethylamine and 16.31 g of benzyl bromide and then heated at reflux for 4 hours. On cooling the mixture to room temperature filtration and evaporation of the filtrate gave a residue which was purified by column chromatography on silica gel, using ethyl acetate/hexane (1:9) for the elution, to give 15.8 g of (E)-benzyl-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerate in the form of a clear oil.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[C:19]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>>[C:19]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])[CH:20]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 388.11 g/mol.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[NH:12]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[C:19](O)=[O:20])[N:14]=[CH:13]1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:15]1[N:14]=[CH:13][NH:12][CH:16]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1c[nH]cn1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1c[nH]cn1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-imidazolyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 247 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:20]([NH:19][CH2:18][CH2:17][Cl:16])=[O:21])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NCCCl
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)NCCCl)c1
Yield: 132.8 %

Procedure:
A solution of (3-Amino-phenyl)-carbamic acid tert-butyl ester (0.5 g, 2.4 mmol) and 1-Chloro-2-isocyanato-ethane (0.25 ml, 2.9 mmol) in dry tetrahydrofuran (20 ml) were stirred at room temperature overnight. Reaction was quenched with water (50 ml) then extracted with dichloromethane (3×50 ml). Combined organics dried (magnesium sulphate) and concentrated in vacuo. The crude residue was purified by column chromatography (eluent 10% ethylacetate in dichloromethane) to afford the title compound (1 g). HPLC retention time 7.45 min. Mass spectrum (ES+) m/z 314 (M+H)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:26])([CH3:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:27].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH3:24][N:21]1[CH2:22][CH2:23][C:11]2[N:10]([CH2:9][C:8]([C:7]3[C:2](=[O:27])[NH:3][CH:4]=[CH:5][CH:6]=3)([OH:26])[CH3:25])[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]=2[CH2:20]1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2Cl)CCN(C)C1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc[nH]c2=O)CCN(C)C1
Temperature: 90 °C
Yield: 36 %

Procedure:
2-(2-Chloropyridin-3-yl)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol (100 mg, 0.277 mmol) and crushed potassium hydroxide (106 mg, 1.89 mmol) in 3 mL tert. butanol were heated at 90° C. for 4 h. The reaction mixture was monitored by TLC and LCMS. The reaction mixture was cooled at RT, diluted with 100 mL brine solution and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (3×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to get the 35 mg of 3-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridin-2(1H)-one as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.79 (d, 1H), 7.35 (m, 2H), 7.17 (s, 1H), 6.93 (d, 1H), 6.34 (t, 1H), 4.61 (d, 2H), 4.3 (d, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.36 (m, 2H), 3.1 (s, 3H), 2.37 (s, 3H), 1.51 (s, 3H). Separation by chiral HPLC provides enantiomers II-143a-b.
Reaction SMILES: [I-:1].[Zn+2:2].[I-].[F:4][C:5]1([F:12])[CH2:10][CH2:9][CH:8](O)[CH2:7][CH2:6]1>C1COCC1>[I-:1].[F:4][C:5]1([F:12])[CH2:10][CH2:9][CH:8]([Zn+:2])[CH2:7][CH2:6]1
Reactant: OC1CCC(F)(F)CC1
Reactant: [Zn+2]
Agent: [I-]
Solvent: C1CCOC1
Product: FC1(F)CCC([Zn+])CC1

Procedure:
The title compound was prepared in an analogous manner to tetrahydro-2H-pyran-4-yl)zinc(II) iodide except that 4,4-difluorocyclohexanol (Affinity Chemicals) was used instead of tetrahydro-2H-pyran-4-ol in Step 1 to afford a 0.26 M solution of (4,4-difluorocyclohexyl)zinc(II) iodide in THF.