Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:31])([F:30])[F:29])=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:46]([O:48][CH:49]([Cl:51])[CH3:50])=[O:47]>C(Cl)(Cl)Cl>[CH3:18][C:15]1([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]2[CH:27]=[C:8]([C:6]([N:5]([CH:2]([CH3:3])[CH3:4])[C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:46]([O:48][CH:49]([Cl:51])[CH3:50])=[O:47])[CH2:33]3)=[O:7])[C:9]([C:28]([F:30])([F:29])[F:31])=[CH:10][C:11]=2[O:16]1
Reactant: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)Cl)C3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-isopropyl-2,2-dimethyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride (3.0 g) in chloroform (25 ml) were added successively triethylamine (0.98 ml) and 1-chloroethyl chloroformate (0.63 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was concentrated to give the title compound (3.55 g) as white amorphous. The obtained title compound was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.Br[C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17](N(C)C)=[O:18].O>C1COCC1.CCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:17]([C:16]2[CH:22]=[CH:23][CH:24]=[CH:14][CH:15]=2)=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CN(C)C(=O)c1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: O=C(c1ccccc1)c1cccc(Br)c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 8.25 g (52.5 mmol) of bromobenzene in 100 mL of THF, 70 mL (105 mmol) of 2.5 M tBuLi in pentane was added dropwise with vigorous stirring for 2 h at −80° C. This mixture was slowly warmed to room temperature and then stirred for 30 min at this temperature. 11.4 g (50 mmol) of 3-bromo-N,N-dimethylbenzamide was added at 0° C., and the resulting mixture was stirred for 12 hr at room temperature. 150 mL of water was added, the organic solvent was evaporated using a rotary evaporator, and the product was extracted with 2×100 mL of dichloromethane. The combined extracts were dried over K2CO3 and then evaporated to dryness. This procedure gave 12.2 g (89%) of 16 which was further used without an additional purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C1COCC1.[Cu]I>[CH3:20][Si:19]([C:17]#[C:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:22])[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
4-Bromobenzaldehyde (1) (185 g, 1.0 mole) was dissolved in THF (1 L) followed by addition of copper (I) iodide (7.6 g, 0.04 mol), dicholobis(triphenylphospine) palladium (II) (14.02 g, 0.02 mol) and triethylamine (151.5 g, 1.5 mol). Ethynyltrimethylsilane (109.1 g, 1.11 mol) was added from addition funnel as a solution in THF (0.2 L). The reaction was stirred at 30° C. for 30 min and then at 25° C. for 20 hours. Analysis by HPLC indicated the completion of the reaction. THF was removed and the residue was treated with hexane (1.8 L). The solid was removed by filtration and the filter cake washed with hexane (0.3 L). The combined hexane solution was washed with water (2×0.5 L). Hexane was removed in a rotovap. The residue was dissolved in EtOH (0.5 L) at 50° C. The solution was then slowly cooled to 16° C. and was stirred for 30 minutes. Product started to crystallize. The mixture was further cooled to 5° C. 1:1 of EtOH/H2O (0.24 L) was added slowly. The mixture was stirred at 5° C. for 30 minutes. Solid was collected by filtration, washed with 4:1 of EtOH/H2O (0.2 L) and dried to provide 137.0 g of product. The mother liquor was concentrated to dryness. The residue was partitioned between hexane (0.5 L) and brine (0.25 L). Hexane layer was separated and concentrated to dryness. The residue was crystallized from hexane (40 ml) and further recrystallized from 4:1 of EtOH/H2O (0.1 L) to provide second crop of aldehyde 2 (27.0 g). The combined yield for aldehyde 2 was 81%. 1H NMR (300 MHz, CDCl3) δ 0.081 (s, 9H), 7.41 (d, 2H, J=8.1 Hz), 7.63 (d, 2H, J=8.4 Hz), 9.81 (s, 1H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>CCCCCC.C1(C)C=CC=CC=1.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=[O:17])=[CH:3][CH:4]=1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C=C2CCCCC2=O)cc1
Temperature: 65 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
In a 1,000-ml, four-necked flask equipped with a mechanical stirrer, a reflux condenser and a thermometer were placed 68 g (0.5 mole) of p-anisaldehyde, 147 g (1.5 moles) of cyclohexanone and then 200 ml of water slowly. Thereto was slowly added, in a water bath, an aqueous solution obtained by diluting 80 g (0.5 mole) of a 25% aqueous sodium hydroxide solution, with 300 ml of water. The system was stirred at 65° C. for 48 hours and cooled to room temperature. To the system were added 400 ml of toluene and 100 ml of water for phase separation. The aqueous layer was re-extracted with 100 ml of toluene. The toluene layers were combined and washed with water and a saturated aqueous sodium chloride solution in this order. The resulting toluene layer was dried over anhydrous sodium sulfate and subjected to vacuum distillation to remove toluene and the excessive (remaining) cyclohexanone. To the crude oil obtained were added 80 ml of toluene and 80 ml of n-hexane for recrystallization, to obtain 80.4 g of yellow crystals. Yield: 74% The purity of the intended product in the crystals was 88% as measured by high performance liquid chromatography.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (400 mg,1.70 mmol) in dichloromethane (15 ml) was treated with morpholinomethyl-polystyrene HL resin (1.00 g, 3.4 mmol/g loading) followed by 4-bromo-3-fluorobenzenesulfonyl chloride (0.50 ml, 930 mg, 3.40 mmol). The resulting solution was stirred at room temperature for overnight (20 hours). The reaction mixture and was then filtered, washed with methanol, and the solvent evaporated in vacuo. The residue was applied to an SCX column eluting first with methanol and then 2M ammonia in methanol. The fractions containing product were collected, combined and evaporated in vacuo to afford a crude product which was dry loaded onto a column and purified further by chromatography using a Flashmaster with an eluting gradient of 0 to 5% methanol in dichloromethane over 40 mins. Fractions containing product were combined and evaporated in vacuo to afford the title compound (E105). MS (ES+) m/e 472/474 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=O)[CH2:14][CH3:15].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH3:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN1CCCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
3-Phenyl-piperidine (4.0 g, 24.81 mmol) and propionaldehyde (1.8 ml, 24.81 mmol) were dissolved in tetrahydrofuran (100 ml). Acetic acid (2.14 ml, 37.21 mmol) and sodium trisacetoxyborohydride (10.515 g, 49.61 mmol) were sequentially added to the reaction mixture and stirred for 1 hour at room temperature. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 solution (50 ml) and diethyl ether (100 ml). The organic phases was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (4.6 g, 87% purity).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol) in 1,2-dichloroethane (5 mL) was added acetic acid (0.2 mmol), formaldehyde (37% water solution, 0.037 mL), and NaBH(OAc)3 (0.2 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (2 M NH3 in MeOH/CH2Cl2) afforded 0.015 g of the title compound. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.45-7.42 (m, 2H), 7.32-7.29 (m, 2H), 7.26-7.19 (m, 3H), 7.03-7.01 (br m, 2H), 5.27 (s, 2H), 2.75-2.68 (m, 4H), 2.64-2.58 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])=[CH:10][CH:9]=1)[OH:7].Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH:6]([OH:7])[C:5]([OH:41])=[O:4])=[CH:13][CH:12]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.022 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)hydroxy-acetic acid methyl ester (Example 154-(3); 5.0 mg, 0.0094 mmol) in methanol (0.15 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (4.8 mg, 99%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.CCOCC>CN(C=O)C.C([O-])(O)=O.[Na+]>[N:10]1([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-chlorobutyrate (0.5 g, 3.32 mmol) in DMF (2 mL), piperidine (0.98 mL, 9.96 mmol), triethylamine (1.4 mL, 9.96 mmol) and a catalytic amount of KI were added and the resulting solution was refluxed overnight. After cooling at room temperature the solution was diluted with a saturated solution of NaHCO3 (10 mL) and extracts with Et2O (3×10 mL). The collected organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the ethyl 4-piperidin-1-ylbutanoate as an oily residue (0.6 g, 3 mmol) pure enough for the next step. To a solution of the ester in dioxane (5 mL), few drops of 37% HCl were added and the solution was refluxed overnight. After cooling at room temperature the solvent was evaporated under vacuum and the residue was dried overnight in oven at 60° C. in vacuo. The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) and NaHCO3 (0.5 g, 6 mmol) was added. After stirring for 2 h, the precipitate was filtered off and the mother liquors concentrated to afford the intermediate sodium 4-piperidin-1-ylbutanoate (0.55 g, 2.84 mmol) as a colourless oil. 1H-NMR (DMSO-d6) δ 3.35 (m, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.15 (t, 2H, J=3 Hz), 1.95 (m, 2H), 1.75 (m, 6H).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:13]1([C:10]2[N:9]3[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]3=[CH:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)NN=Cc1c[nH]c(-c2ccccc2)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ncc2cnc(-c3ccccc3)n12

Procedure:
A 7.76 gm. portion of 3-(2-phenyl-4-imidazolylmethylene)carbazic acid ethyl ester in 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 245°-248° C.
Reaction SMILES: [C:1]([O-:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CS([C@@:15]1(O)[C@:19](S(C)(=O)=O)(O)[C@@H:18]([CH:25](S(C)(=O)=O)[OH:26])[O:17][C@H:16]1[N:31]1[CH:38]=[C:37]([CH3:39])[C:35](=[O:36])[NH:34][C:32]1=[O:33])(=O)=O.Br.CC(O)=O>CN(C=O)C.[Zn]>[C:1]([CH:25]([OH:26])[C@H:18]1[O:17][C@@H:16]([N:31]2[CH:38]=[C:37]([CH3:39])[C:35](=[O:36])[NH:34][C:32]2=[O:33])[CH:15]=[CH:19]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](C(O)S(C)(=O)=O)[C@](O)(S(C)(=O)=O)[C@]2(O)S(C)(=O)=O)c(=O)[nH]c1=O
Reactant: O=C([O-])c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C=C[C@@H](C(O)C(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 5.5 h

Procedure:
To a slurry of powdered sodium benzoate (3.5 g, 24.3 mmol) in DMF (25 ml) at 90° C. was added tris(methanesulfonyl)-5-methyluridine (IX, 5.0 g, 10.2 mmol). The reaction was stirred for 5.5 hours at 90° C. HBr/HOAc (30-32%, 5 ml, 25.1 mmol) was added and the reaction was stirred for one hour. The reaction mixture was cooled to 25° C. and zinc dust (2.0 g, 30.6 mmol) was added. The reaction was stirred for 30 minutes. The excess zinc was removed by filtration and washed with 2×100 ml methanol. To the filtrate was added 100 ml ice-cold water. The resulting slurry was stirred at 0° C. for 30 minutes and then filtered, dried to give 5'-benzoyl-d4T, 2.34 g (71%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:28][NH:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:35]4[CH2:36][CH2:37][N:32]([C:27]5[C:26]6[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=6)[NH:29][N:28]=5)[CH2:33][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperazin-1-yl-1H-indazole (Table No.1, SM 4) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)(=[O:34])=[O:33]
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2Cl)cc1)N1Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 128.6 %

Procedure:
A mixture of 0.13 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.21 g of 2-chlorobenzenesulfonyl chloride, 0.12 g of triethylamine and 5 mg of N,N-dimethylaminopyridine in 2 ml of methylene chloride is stirred at room temperature for 18 hours. The mixture is partitioned between 1N NaOH and ethyl acetate. The organic layer is washed with 50% NH4Cl and brine, dried over Na2SO4 and evaporated to give 0.26 g of the desired product as a yellow solid. MS(CI):663(M+H; C35).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:23]>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:23][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and 3-methyl-L-valine methyl ester hydrochloride (1:1) (CAN 63038-27-7) as starting materials, and isolated (98 mg, 91%) as light yellow oil; LC-MS (UV peak area, ESI) 100%, 362.2081 (M+H).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13].[CH2:20](O)C>>[N:11]([CH:14]([CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[CH3:2])[CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13]
Reactant: CCO
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1ccccc1C=O
Agent: [Na]
Product: CCOC(=O)C(N=[N+]=[N-])C(C)c1ccccc1C
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Sodium pieces (5.15 g, 240 mmol) were added in portions to ethanol (157 ml). The resulting solution was cooled in an ice/acetone bath to −15° C. and then over one hour a mixture of 2-methylbenzaldehyde (7.209 g, 60 mmol) and ethyl azidoacetate (30.980 g, 240 mmol) was added at a rate that maintained the temperature below 10° C. After 3 hours, the solution was stored at 5° C. for two days to give pure product as yellow crystals.
Reaction SMILES: [N:1]([C@H:4]([C:23](=[O:36])N1[C@H](C2C=CC=CC=2)COC1=O)[C@H:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=1)[CH3:6])=[N+:2]=[N-:3].OO.[OH-:39].[Li+]>O.C1COCC1>[N:1]([C@@H:4]([C@H:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:8]=1)[CH3:6])[C:23]([OH:36])=[O:39])=[N+:2]=[N-:3]
Reactant: C[C@@H](c1cn(C(=O)OC(C)(C)C)c2ccccc12)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1c1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1cn(C(=O)OC(C)(C)C)c2ccccc12)[C@H](N=[N+]=[N-])C(=O)O
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 3-((2S,3S)-3-azido-4-oxo-4-((R)-2-oxo-4-phenyloxazolidin-3-yl)butan-2-yl)-1H-indole-1-carboxylate (3.38 g, 6.90 mmol) in Water (29 mL) and THF (86 mL) at 0° C. was added hydrogen peroxide (4.67 ml, 45.7 mmol), then lithium hydroxide (0.331 g, 13.81 mmol). The reaction was stirred for 2 h. The reaction was quenched with Na2SO3 (7 g) in 40 mL water. The reaction was stirred for 30 min at rt. The solvent was removed under vacuum and then the reaction was diluted with EtOAc and water. The pH was adjusted to 2. The organic phase was collected, washed with brine, dried over sodium sulfate and concentrated under vacuum to give a residue which was triturated in Et2O to give a solid which was collected by filtration and dried to give (2S,3S)-2-azido-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid, 2.38 g (100%). ESI-MS(−) m/z 343.3 (M−H). 1H NMR (500 MHz, chloroform-d) d 8.15 (d, J=5.5 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.58-7.55 (m, 1H), 7.33 (td, J=7.7, 1.1 Hz, 1H), 7.27-7.23 (m, 1H), 4.29 (d, J=6.5 Hz, 1H), 3.68 (quin, J=6.9 Hz, 1H), 1.70 (s, 9H), 1.51 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[I:22]N1C(=O)CCC1=O.[NH4+].[OH-]>CC(O)=O>[CH2:1]([C:8]1[CH:9]=[C:10]([I:22])[C:11]([OH:14])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cn1
Reactant: O=C1CCC(=O)N1I
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Oc1ncc(Cc2ccccc2)cc1I
Reaction time: 8 h

Procedure:
To a yellow solution of 5-benzylpyridin-2-ol (1.10 g, 5.94 mmol) in 22 mL AcOH under Ar was added 1.5 mL TFA, followed by N-iodosuccinimide (1.34 g, 5.94 mmol). The red homogeneous solution was allowed to stir overnight, poured onto ice and neutralized with conc. NH4OH. The solids were collected by filtration, rinsed with water, treated with MeOH/DCM, dried over sodium sulfate, and evaporated. The resulting brown solid was purified by silica gel chromatography (ISCO, 80 g, 0-70% 90/10 DCM/MeOH in DCM) to give 5-benzyl-3-iodopyridin-2-ol as a yellow/brown solid. MS (ESI) m/z: Calculated: 311.0; Observed: 311.9 (M++1).