Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=3[CH:38]=2)[C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1([NH2:48])[CH2:47][CH2:46]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34]([NH:35][CH3:36])=[O:37])[C:23]=3[CH:38]=2)[CH:15]=[C:11]([C:12](=[O:13])[NH:48][C:45]2([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH2:47][CH2:46]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(OCc4ccccc4)c3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)cc(OCc4ccccc4)c3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.40 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (0.064 g, 0.47 mmol, 1.2 eq) (60% purity), HOBT (0.68 g, 0.012 mmol, 1.7 eq), EDC.HCl (0.064 g, 0.72 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.26 g, 2.0 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and preparative HPLC. Yield: 0.17 g (70%). 1H NMR (400 MHz, DMSO-d6): δ 1.26-1.27 (m, 2H), 1.54-1.56 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (s, 3H), 5.26 (s, 2H) 7.13-7.15 (q, 1H, J=4.4 Hz), 7.30-7.43 (m, 6H), 7.58 (d, 4H), 7.65-7.69 (t, 2H, J=3.9 Hz), 7.74-7.79 (d, 1H, J=8.0 Hz), 7.97-8.01 (m, 2H), 8.43-8.48 (dd, 2H, J=4.89 Hz), 9.186 (s, 1H). LCMS: (ES+) m/z=626 (M+H) Ascentis Express C18 (5.0×2.1-2.7 μm). Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH. Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH. Flow: 5 ml/Min.
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21](P(=O)(OCC)OCC)[P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Li+].CCOCC>O1CCCC1.O>[C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCC#Cc1ccccc1/C=C/P(=O)(OCC)OCC
Yield: 80.1 %

Procedure:
Tetraethyl [2-[2-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (2.0 g, 3.61 mmol) prepared according to Example 9 was dissolved in tetrahydrofuran (26 ml). Lithium hydroxide (0.152 g, 3.62 mmol) was dissolved in water (10 ml) and added to the tetrahydrofuran solution. After stirring the reaction overnight, ether was added, and the aqueous phase was extracted with ether. The combined ether layers were dried (MgSO4) and stripped down. The residue was chromatographed on silica eluting with 3% ethanol in hexane. Tlc on silica, developed in 5% ethanol in hexane, was used to identify product, Rf =0.04. Impure fractions were combined and rechromatographed as necessary to give 1.21 g, 2.89 mmol, 80% yield of the product as a pale yellow liquid; 1H NMR (CDCl3) ∂0.88 (m, 3H), 1.15 to 1.81 (several m, 24H), 2.46 (t, J=7.1 Hz), 4.15 (m, 4H), 6.37 (t, J=18 Hz, 1H), 7.26 (m, 2H), 7.42 (m, 1H), 7.54 (m, 1H), 7.95 (dd, J=23.0, 17.7 Hz, 1H); EI mass spectrum m/z 419 (M+H)+.
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2]CC.O.[CH3:10][CH:11]([NH2:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:10]([P:1](=[O:2])([O-:5])[O-:8])[CH3:11].[CH3:10][CH:11]([NH3+:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:10][CH:11]([NH3+:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOP([O-])OCC
Reactant: CC(N)COc1ccccc1
Solvent: CCO
Solvent: O
Product: CC([NH3+])COc1ccccc1
Product: CCP(=O)([O-])[O-]
Yield: 81.9 %

Procedure:
A mixture of 13.81 g. (0.1 moles) of diethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 15.12 g. (0.1 moles) of 1-methyl-2-phenoxyethyl amine and 30 ml. of ethanol as described in Example 1. 21.4 g. of 1-methyl-2-phenoxyethyl-ammoniumethyl phosphonate is obtained. Yield: 81.9%. Melting point: 95°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:12]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNC12CCCCC2
Agent: O=S(=O)(O)O
Product: Cl
Product: Clc1ccc(C2=CCNC23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 4-(4-chlorophenyl)-4-hydroxy-1azaspiro[4.5]decane (2.2 g) was dissolved in concentrated sulphuric acid (27 ml) and the solution was stirred at ambient temperature for 1 hour. The mixture was poured onto ice to give a white precipitate which was collected by filtration, dissolved in water, and basified by the addition of 5M aqueous sodium hydroxide solution. The product was extracted into ether (3×200 ml) and the extracts were combined, dried over magnesium sulphate, and concentrated in vacuo to 100 ml. The solution was saturated with hydrogen chloride and the resulting solid was collected by filtration and dried in vacuo at 60° C. for 7 hours to give 4-(4-chlorophenyl)-1-azaspiro[4.5]dec-3-ene hydrochloride as a white solid. Yield 1.1 g, mp 225°-233° C.(dec).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CON(C)[C:9]([C:11]1[C:16]([NH2:17])=[N:15][CH:14]=[C:13]([C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:33])[N:12]=1)=[O:10].Cl>C1COCC1>[NH2:17][C:16]1[C:11]([C:9]([CH:1]2[CH2:3][CH2:2]2)=[O:10])=[N:12][C:13]([C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:33])=[CH:14][N:15]=1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1nc(-c2cc(S(=O)(=O)N3CCOCC3)ccc2C)cnc1N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(C(=O)C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1M solution of cyclopropyl magnesium bromide in THF (0.21 ml, 0.21 mmol) is added to a solution of 3-amino-6-[2-methyl-5-(morpholine-4-sulfonyl)-phenyl]-pyrazine-2-carboxylic acid methoxy-methyl amide (Intermediate C) (0.058 mg, 0.14 mmol) in anhydrous THF (3 ml) under N2. The orange solution is stirred at room temperature for 2 hours after which time a 1M solution of cyclopropyl magnesium bromide in THF (0.21 ml, 0.21 mmol) is added. The orange solution is stirred at room temperature for 1 hour. 1M HCl (15 ml) is added, and the product extracted into EtOAc (30 ml), dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (SiO2, 33-50% EtOAc in iso-hexane) yields the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (1H, s), 7.92 (2H, bs), 7.79 (1H, s), 7.70-7.63 (2H, m), 3.64-3.62 (4H, m), 3.49-3.43 (1H, m), 2.90 (4H, bs) 2.54 (3H, s), 1.09-1.01 (4H, m); MS m/z 403 [M+H]+
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][NH:2]2.[CH:10](=O)[CH3:11].[H][H]>CO.[Pd]>[CH2:10]([N:2]1[CH2:3][CH2:4][CH:5]2[CH2:9][CH:1]1[CH2:8][CH2:7][CH2:6]2)[CH3:11]
Reactant: C1CC2CCNC(C1)C2
Reactant: [H][H]
Reactant: CC=O
Agent: [Pd]
Solvent: CO
Product: CCN1CCC2CCCC1C2
Yield: 72 %

Procedure:
To a solution (2 ml) of 2-azabicyclo[3.3.1]nonane (100 mg, 0.62 mmol) in methanol were added a 10% acetaldehyde solution (5 ml) and 10% palladium on activated carbon (100 mg) and the mixture was stirred for 3 hours under the hydrogen atmosphere. The reaction mixture was filtered by means of suction, and the filtrate was concentrated under a reduced pressure. A saturated aqueous solution of sodium bicarbonate (10 ml) was added to the residue, followed by extraction with chloroform (3×20 ml). The extrant was dried (over MgSO4), followed by removal of the solvent and purification of the residue with silica gel column chromatography (chloroform-methanol-triethylamine=100:9:1), to obtain 2-ethyl-2-azabicyclo[3.3.1]nonane (68 mg, 72%) as a colorless oily material.
Reaction SMILES: [OH-].[Na+].CO[C:5]([NH2:7])=[NH:6].OS(O)(=O)=O.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1>O>[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1)(=[NH:6])[NH2:7]
Reactant: COC(=N)N
Reactant: O=C(O)CCC1CCNCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)N1CCC(CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 50.9 %

Procedure:
20 ml of 2 N sodium hydroxide was stirred with ice-cooling, and 3.4 g of o-methylisourea sulfate and 3.1 g of piperidine-4-propionic acid were added to the aqueous sodium hydroxide solution. To the mixture was then added 5 ml of water, and the resulting mixture was stirred at room temperature for 19 hours. The product precipitated was separated by filtration and washed with a small amount of cold water three times, then with acetone and finally with ether to obtain 2.0 g of 1-amidino-4-piperidinepropionic acid as colorless crystals having a melting point of 294° C. (decomposed).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=3)[CH2:3][CH2:2]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(NC2CCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.2 %

Procedure:
A mixture of methyl 6-(4-piperidylamino)nicotinate (1.0 g), 4-chlorobenzoic acid (699 mg), HOBt (603 mg) and EDCI (693 mg) in DMF (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (7:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinate (1.21 g)
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27](B(O)O)[CH:26]=1>>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:27]5[CH:26]=[N:25][C:34]6[C:29]([CH:28]=5)=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cnc6ccccc6c5)n4n3)cc2)CC1

Procedure:
[4-(4-Methyl-piperazin-1-yl)-phenyl]-(7-quinolin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine and 3-quinolineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (49 mg, 40%). m.p.=235-241° C.; LCMS (m/e) 436 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.38 (s, 1H), 9.34 (s, 1H), 8.76 (s, 1H), 8.13 (d, 1H, J=9.1 Hz), 7.85 (d, 1H, J=7.0 Hz), 7.80-7.69 (m, 1H), 7.63-7.52 (m, 3H), 7.25-7.17 (m, 1H), 6.98 (d, 2H, J=7.9 Hz), 6.93-6.86 (m, 1H), 6.70 (s, 1H), 3.29-3.19 (m, 4H), 2.69-2.57 (m, 4H), 2.39 (s, 3H).
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:19]1(C)[CH:24]=[CH:23]C=[CH:21][CH:20]=1.[C:26]([O:29][CH2:30]C)(=[O:28])[CH3:27]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[C:20]1[CH:19]=[CH:24][CH:23]=[C:27]([C:26]([O:29][CH3:30])=[O:28])[CH:21]=1)=[O:5]
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1
Reactant: Cc1cccc(C=O)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: COC(=O)c1cccc(-c2c(C)cccc2C=O)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 65 %

Procedure:
A mixture of 2-bromo-3-methylbenzaldehyde (0.30 g, 1.51 mmol), tris(dibenzylidenacetone)dipalladium (0) (0.055 g, 0.060 mmol), 2-(dicyclohexylphosphino)biphenyl (0.032 g, 0.091 mmol), tripotassium phosphate (0.64 g, 3.0 mmol), 3-(methoxycarbonylphenyl)boronic acid (0.35 g, 1.96 mmol) and toluene (6 mL) was stirred under an argon atmosphere at 90° C. for 17 hrs. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=4/1) to give the title compound (0.25 g, yield 65%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH3:36]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4C)c(Cl)c3)c2cc1OC
Yield: 85.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methylphenyl)methanol (28 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 75%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:7]=[N:8][CH:9]=1.I[CH3:24]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[N:16]([CH3:24])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:7]=[N:8][CH:9]=1
Reactant: CI
Reactant: Cc1cc(C(=O)c2cncc(Br)c2)cc2oc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cncc(Br)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.18 g (4.00 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 1.27 g (3.80 mmol) 6-(5-bromo-pyridin-3-carbonyl)-4-methyl-3H-benzoxazol-2-one in 5 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.32 mL (5.00 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto ice water and the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:30]([O:29][C:27]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)(=[O:23])=[O:24])=[O:28])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2ccc(Cn3cncn3)cc2)c(S(N)(=O)=O)s1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2cncn2)cc1
Reaction time: 8 h
Yield: 9.2 %

Procedure:
59 mg (0.16 mmol) of the crude 3-(4-[1,2,4]triazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide from step (c) above was mixed with butyl chloroformate (31 μL, 0.24 mmol) and 4-dimethylaminopyridine (2 mg, 16 μmol) in 5 mL of triethylamine at 0° C. The reaction mixture was stirred overnight and then diluted with ethyl acetate, washed with water and dried over K2CO3. The reaction mixture was then separated on a silica column (dichloromethane+15% methanol), circular chromatography (dichloromethane+10-15% methanol and preparative LC-MS to yield 7.0 mg of the title compound (9% isolated yield).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7]Br.[CH3:29][C:30]1([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[CH3:1][N:2]([CH3:28])[C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][N:33]1[CH2:34][CH2:35][C:30]([OH:36])([CH3:29])[CH2:31][CH2:32]1
Reactant: CN(C)C(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: CC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C(CCCN1CCC(C)(O)CC1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 16 h
Yield: 34.9 %

Procedure:
A solution of 107 mg (0.23 mmol) of (rac)-5-bromo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid dimethylamide in 4 ml of CH3CN was treated with 115 mg (0.28 mmol) of 4-methyl-piperidin-4-ol (intermediate 8) and 63 mg (0.46 mmol) of potassium carbonate. After 16 h at RT, the reaction mixture was diluted with AcOEt and a white solid was filtered off. The filtrate was evaporated and chromatographed by amine-silica gel column (AcOEt:MeOH 19:1) to yield 40 mg (35%) of the title compound as yellow oil. MS: 499.2 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[N:3]1[C:12]2[C:7](=[CH:8][C:9](I)=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1.[CH2:19]([OH:22])[C:20]#[CH:21].O.C(OC(C)C)(C)C>CC#N.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]([CH3:18])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:21]#[C:20][CH2:19][OH:22])=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1
Reactant: C#CCO
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: CN(C)n1cc(C(=O)O)c(=O)c2cc(C#CCO)ccc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 181.9 %

Procedure:
To a solution of 1-dimethylamino-6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2.77 g, 7.73 mol) in MeCN (70 ml), CuI (0.15 g, 0.773 mol) and TEA (37.5 ml, 270 mol) were added and stirred for 20 minutes and then warmed up to 50° C. To the reaction mixture propargyl alcohol (1.08 ml, 2.4 mmol) and Pd(PPh3)2Cl2 (0.27 g, 0.39 mol) were added and stirred at 50° C. for 3 hours. Then water (130 ml) and diisopropyl-ether (100 ml) were added, the pH was adjusted to 12, the layers were separated and H2O layer extracted with diisopropyl-ether (2×50 ml). To the water layer EtOH (14 ml) and charcoal were added, heated to the reflux temperature, and filtered through celite. Then the pH of H2O solution was adjusted to 6, extracted with DCM (200 ml), combined organic layers were evaporated to obtain the crude product. Precipitation from DCM-hexane afforded the title product (1.25 g, 56%).
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH:3]1[CH3:7].[CH3:24]I>>[CH3:24][O:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH:3]1[CH3:7]
Reactant: CI
Reactant: CC1OCCC1(O)c1ccc(Sc2ccc3ccccc3c2)s1
Product: COC1(c2ccc(Sc3ccc4ccccc4c3)s2)CCOC1C
Yield: 75 %

Procedure:
Using the procedure described in Example 1, (2RS,3RS)-3-hydroxy-2-methyl-3-[5-(naphth-2-ylthio)thien-2-yl]tetrahydrofuran was reacted with methyl iodide to give (2RS,3RS)-3-methoxy-2-methyl-3-[5-(naphth-2-ylthio)thien-2-yl]tetrahydrofuran in 75% yield as an oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:19]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:24])[N:18]1[CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1nc(CO)cc(C)c1C#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc(CN2C(=O)c3ccccc3C2=O)cc(C)c1C#N
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a stirred solution of 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (1.50 g, 8.42 mmol), phthalimide (1.3 g, 8.84 mmol) and triphenylphosphine (2.3 g, 8.77 mmol) in Tetrahydrofuran (THF) (50 mL) at 0° C. in an ice bath was added dropwise DIAD (1.8 mL, 9.26 mmol). Within minutes a white suspension formed. Additional THF (˜50 mL) was added to allow stirring. The reaction was allowed to warm to RT and stirred for 3 h. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum. The remaining solid was triturated with a small volume of EtOAc, filtered, washed with a small volume of EtOAc, then dried under vacuum to give the product 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-methoxy-4-methylnicotinonitrile (2.12 g, 6.90 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.00-7.92 (m, 2H), 7.92-7.87 (m, 2H), 7.15 (s, 1H), 4.86 (s, 2H), 3.74 (s, 3H), 2.43 (s, 3H). MS(ES)+ m/e 308.2 [M+H]+.