Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3](O)[CH3:4].[CH3:7][S:8]([OH:11])(=[O:10])=[O:9]>>[CH3:7][S:8]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][O:9][S:8]([CH3:7])(=[O:11])=[O:10])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)O
Reactant: CC(O)CCO
Product: CS(=O)(=O)OCCCCOS(C)(=O)=O

Procedure:
Into a four-necked flask, fitted with a mechanical stirrer, condenser, thermometer and a Nitrogen inlet was added 665.53 g (1.40 moles) of PPG-4-N-Methyl-N,N-Diethanolamine Adipate oligomer, from Example 2, and 240.43 g (2.67 moles) of 1,3-Butanediol. With the reaction mixture at 30-35° C., 131.89 g (1.37 moles) of Methanesulfonic Acid (MSA) was slowly added to neutralize the amine. The reaction was monitored by measuring the Acid Value and Base Value of the reaction mixture over time. When Methanesulfonic salt of PPG-4-N-Methyl-N,N-Diethanolamine Adipate oligomer was formed, 120.51 g (1.30 moles) of Epichlorohydrin was charged. The reaction temperature was increased to 85-90° C. and kept under Nitrogen blanket while it stirred for the next 6 hours. Reaction was monitored by the drop in Acid Value. When the acid value stabilized, 541.63 g (1.6105 moles) of Cinnamidopropyldimethylamine was charged (Cinnamidopropyldimethylamine was prepared as disclosed in example 1 in U.S. Pat. No. 5,633,403). The reaction mixture was stirred for 6 hours at 85-90° C. and was monitored by a drop in Base Value. When the base value drop stabilized, the product was diluted with water to 64-68% actives to improve fluidity. The resulting product, [Poly(N-Hydroxypolyoxypropylethyl) N-Adipyl-Poly-Oxypropyl)-N-Methyl-N-(2,Hydroxy-3-Cinnamidopropyl Dimethyl Ammonium Chloride) Methane Sulfonate] was obtained as a viscous yellow liquid.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]1[N:29]=[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]3[O:38][CH2:39][O:40][C:34]=3[CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=2)[N:21]=1>CC(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:20]2[N:29]=[C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=3)[N:21]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(C#N)ccc3n2)CC1
Temperature: 25 °C
Yield: 83 %

Procedure:
3.71 g of ethyl isonipecotate, 2.38 g of triethylamine and 10 ml of 2-propanol were added to 1 g of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 1 hour and cooled to room temperature. The crystals thus precipitated were recovered by filtration and washed with water and ether successively to give 1.126 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:30]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:29]([F:37])[C:8]2[NH:9][C:10]([NH:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[Cl:28])=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>>[Cl:28][C:14]1[C:15]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:10]1[NH:9][C:8]2[C:29]([F:37])=[C:30]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)[nH]c2c(F)c1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)(F)F)c(F)c3[nH]2)c1Cl

Procedure:
The subtitle compound is prepared from 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2,2-trifluoroethoxy)-7-fluoro-1H-benzimidazole-5-carboxylic acid methyl ester and NaOH in analogy to example 28a.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17](O)(C#C)C.Cl>C(N(CC)CC)C.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.[Cu](I)I>[F:8][C:7]1[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=[CH:3][C:2]=1[C:16]#[CH:17]
Reactant: C#CC(C)(C)O
Reactant: CCCCCCOc1cccc(Br)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: C#Cc1cccc(OCCCCCC)c1F
Temperature: 0 °C
Yield: 63.1 %

Procedure:
117 g of potassium carbonate and 55.6 g of bromohexane are added to a solution of 53.6 g of 3-bromo-2-fluorophenol in 650 ml of acetone, and the mixture is refluxed for 8 hours. The mixture is filtered, evaporated to ⅓ of the original volume and poured into 600 ml of water. The pH is adjusted to 1 using hydrochloric acid, and the mixture is extracted three times with 150 ml of tert-butyl methyl ether each time. The combined organic phases are concentrated under reduced pressure, and the residue is subjected to vacuum distillation (103° C.; 1 mbar), giving 67 g of 6-bromo-2-hexyloxyfluorobenzene as a colorless oil. 1H-NMR (CDCl3): 6.9-7.1 (m; 3H); 4.0 (t; 2H), 0.9-1.8 (m, 11H), 19F-NMR (CDCl3): −128 ppm. A solution of 67.3 g of 6-bromo-2-hexyloxyfluorobenzene, 24.7 g of 2-methyl-3-butyn-2-ol [115-19-5], 0.7 g of bis(triphenylphosphine)palladium(II) chloride and 0.7 g of copper iodide in 340 ml of triethylamine is refluxed for 5 hours. The mixture is then poured into 1.5 of ice-water, the pH is adjusted to 1 using hydrochloric acid, and the mixture is extracted three-times with 200 ml of tert-butyl methyl ether each time. The combined organic phases are dried under reduced pressure. The crude 4-(2-fluoro-3-hexyloxyphenyl)2methyl-3-butyn-1-ol is refluxed for 3 hours in 1000 ml of toluene together with three mole-equivalents of sodium hydroxide. The mixture is filtered and washed with dilute hydrochloric acid, the solvent is removed by distillation, and the residue is distilled (90° C.; 0.5 mbar), giving 34 g of 1-(2-fluoro-3-hexyloxyphenyl)ethyne.
Reaction SMILES: I[CH3:2].[SH:3][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[N:6][N:5]=1.[OH-].[Na+]>CO>[CH3:2][S:3][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[N:6][N:5]=1
Reactant: CCCCn1cnnc1S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cnnc1SC

Procedure:
Iodomethane (9.05 g. or 0.0637 mole) was added to a solution of 10 g. of 3-mercapto-4-n-butyl-1,2,4-triazole, methanol (100 ml.), and sodium hydroxide (2.55 g. or 0.0637 mole). This solution was then refluxed for 2 hours. The solvent was then removed in vacuum and the residue was dissolved in benzene. This solution was washed with water, dried and the benzene removed in vacuum. The residual oil was distilled to give 3-methylmercapto-4-n-butyl-1,2,4-triazole, b.p. 128°-131° C./ 2 mm. The structure was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: O.O.[C:3]([OH:8])(=O)[C:4](O)=[O:5].C(O)(=O)C(O)=O.Cl.[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]>O>[OH:5][C:4]1[C:3]([OH:8])=[N:23][C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:22]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: O
Product: Oc1nc2ccccc2nc1O
Temperature: 90 °C
Yield: 95.8 %

Procedure:
To a 2 L flask were added 280.0 g of oxalic acid dihydrate (2.221 moles) and then 1 L of distilled water. Then the mixture was heated to 90° C. After complete dissolution of oxalic acid, 400 mL of concentrated hydrochloric acid was added, followed by addition of 220.0 g of o-phenylenediamine (2.034 moles). The temperature was maintained at 90° C. for 30 minutes with continuous stirring. Off-white crystals were formed. After cooling to room temperature, the off-white crystals were collected by filtration, washed first with water, then with methanol and dried under reduced pressure to give 315.8 g (96%) of off-white needles: mp>350° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:23])([C:14]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])=[O:15])[CH2:6][CH2:5]2.[O:25]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:7]([CH3:23])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:24])[C:14]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCOCCO)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCOCCO)=C(C)C1=O

Procedure:
Oxidation as described in protocol B, using 98.1 mg (0.305 mmol) of 6-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 368 mg CAN (0.671 mmol) yielded 2-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N=C2CCCC(=O)C2)=[CH:4][CH:3]=1.[OH2:17]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:3]1[CH2:4][CH2:5][CH2:6][C:7](=[O:17])[C:2]2=1
Reactant: O=C1CCCC(=NNc2ccc(Br)cc2)C1
Reactant: O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: O=C1CCCc2[nH]c3ccc(Br)cc3c21

Procedure:
The product of Stage (i) (1.5 g) was heated under reflux with dry zinc chloride (16 g) in glacial acetic acid (75 ml) for 24 h. The mixture was cooled, poured into water (200 ml), and the resulting solid filtered off and dried (0.95 g). Purification by flash chromatography (E) gave the title compound as a solid (125 mg). T.l.c. (F), Rf 0.65
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[CH3:17])[N:5]=[C:4]([O:18][CH2:19][CH2:20][OH:21])[N:3]=1.Br[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:18][CH2:19][CH2:20][O:21][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[N:5]=[C:6]([NH:9][CH2:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[CH3:17])[C:7]=1[CH3:8]
Reactant: Brc1ccc2cccnc2n1
Reactant: Cc1nc(C)c(CNc2nc(OCCO)nc(Cl)c2C)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CNc2nc(OCCOc3ccc4cccnc4n3)nc(Cl)c2C)s1
Reaction time: 8 h

Procedure:
2-[(4-chloro-6-{[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-5-methylpyrimidin-2-yl)oxy]ethanol G1 (17 mg, 0.052 mmol) and 2-bromo-1,8-naphthyridine (11 mg, 0.053 mmol) were placed in a test tube and dissolved in THF (1 mL). A 2 M solution of NaHMDS in THF (39 μL, 0.078 mmol) was added at ambient temperature, and the reaction was stirred overnight. Solvent was then removed, and the product was purified by silica gel flash column chromatography (EtOAc/hexanes gradient). 10 mg (42%) of G2 were isolated as an off-white solid. 1H NMR (499 MHz, DMSO-d6): δ 8.97 (s, 1H); 8.56 (d, J=8.03 Hz, 1H); 8.44 (d, J=8.81 Hz, 1H); 7.89-7.84 (m, 1H); 7.62 (dd, J=7.95, 4.62 Hz, 1H); 7.26 (d, J=8.79 Hz, 1H); 4.78 (d, J=5.18 Hz, 2H); 4.66 (d, J=4.97 Hz, 2H); 4.57 (d, J=5.78 Hz, 2H); 2.47 (s, 3H); 2.30 (s, 3H); 2.01 (s, 3H). HRMS (Electrospray): m/z 457.1206 (MH+).
Reaction SMILES: [NH2-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.Cl[CH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH:4]1[N:12]([CH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCCC1CCCl
Reactant: c1ccc(NC2Cc3ccccc3C2)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCCC1CCN(c1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of sodamide (256 mg, 6.58 mmol) in toluene (10 mL) was added a solution of indan-2-yl-phenyl-amine (7; 1.0 g, 4.78 mmol) in toluene (5 mL) at 0° C. The reaction mixture was stirred at rt for 3 hours. A solution of 2-(2-chloroethyl)-1-methyl-pyrrolidine hydrochloride (18; 0.808 g, 4.39 mmol) in toluene (5 mL) was added to the reaction mixture and the resulting mixture was refluxed for 16 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography on neutral alumina eluting with 0.8% methanol-DCM to provide compound 19.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O>CS(C)=O>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Yield: 43 %

Procedure:
A solution of 5-chloro-2-nitrophenylamine (4.3 g, 25 mmol) and morpholine (4.4 mL, 500 mmol) in dimethylsulfoxide (DMSO) (25 mL) was stirred at 90° C. for 16 h. The reaction mixture was poured into water (500 mL) and the resulting precipitate was collected by vacuum filtration and recrystallized from methanol (300 mL) to yield the product as orange crystals (2.4 g, 43%). M.P. 177–178° C. (lit. 184–186° C.). See, Polymers 36:3401–3408 (1995).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:16]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][C:18]([O:20]C)=[O:19].C[O-].[Na+].[OH-].[Na+]>CO.O>[CH2:22]([C:16]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[N:2]=[N:3][C:17]=1[C:18]([OH:20])=[O:19])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 4-azido-N-ethylbenzamide (1.00 g) obtained in Example 43a) and methyl 3-oxoheptanoate (1.10 g) in methanol (50 ml) was added a solution of sodium methoxide in methanol (1.35 g, 28%). The reaction mixture was stirred at room temperature for 8 hr and at 70° C. for 3 hr, and 1M aqueous sodium hydroxide solution (11 ml) was added. The reaction mixture was stirred at 70° C. for 1 hr, cooled to room temperature, diluted with water, and methanol was evaporated under reduced pressure. The residual aqueous solution was acidified (pH=1) with 1M hydrochloric acid under ice-cooling, the insoluble material was collected by filtration and washed with water to give the title compound as a brown powder (1.66 g, 99%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=1>CC#N>[CH2:5]([O:4][C:2]([C:11]1[N:12]([CH3:13])[C:8]([Br:7])=[CH:9][N:10]=1)=[O:3])[CH3:6]
Reactant: Cn1cncc1Br
Reactant: CCOC(=O)Cl
Solvent: CC#N
Product: CCOC(=O)c1ncc(Br)n1C
Temperature: 25 °C
Yield: 55.3 %

Procedure:
Ethyl chloroformate (1.19 mL, 12.4 mmol) in MeCN (5 mL) was added dropwise to a 1.00 g (6.21 mmol) of 5-bromo-1-methyl-1H-imidazole (Aldrich) in 30 mL of MeCN under N2. The mixture was stirred and allowed to warm to rt overnight. The mixture was concentrated and the residue was treated with 2M NaOH (100 mL) and extratcted with CH2Cl2 (3×100 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, concentrated, and chromatographed (0-50% EtOAc in hexanes) to give the 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester as a yellow oil (800 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([F:46])=[CH:30][N:29]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH3:44][C:37]1([CH3:45])[CH2:36][C@H:35]([NH:34][C:32]2[C:31]([F:46])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][OH:18])=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[CH:7]=3)[N:33]=2)[CH2:43][C@H:42]2[N:38]1[CH2:39][CH2:40][CH2:41]2
Reactant: Cn1nnn(-c2cc(N)ccc2OCCO[Si](C)(C)C(C)(C)C)c1=O
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)ccc2OCCO)c1=O
Yield: 20 %

Procedure:
The general displacement procedure was described herein was used with 1-(5-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (382 mg, 1.1 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (350 mg, 1.1 mmol) and pTsOH.H2O (398 mg, 2.1 mmol) in IPA (10 mL) at reflux to give the product (113 mg, 21% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 95:5) as eluent.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@@H:19]1[CH2:23][O:22]C(C)(C)[O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO.Cl>[CH2:1]([O:17][CH2:18][C@@H:19]([OH:20])[CH2:23][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H]1COC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Reaction time: 12 h
Yield: 81.1 %

Procedure:
A mixture of 28.2 g of (R)-4-[(hexadecyloxy)methyl]-2,2-dimethyl-1,3-dioxolane in 189 ml of methyl alcohol and 21 ml of 1N hydrochloric acid is stirred at reflux for 2.5 hours followed by 12 hours at ambient temperature. The reaction is cooled, filtered and the cake washed with cold methyl alcohol then dried to give 20.3 g of the desired product as white plates, m.p. 63°-64° C.
Reaction SMILES: Cl.C([O:6][C:7](=[O:28])[CH2:8][NH:9][S:10]([C:13]1[CH:22]=[C:21]2[C:16]([C:17]([Cl:27])=[CH:18][N:19]=[C:20]2[NH:23][C:24]([NH2:26])=[NH:25])=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.[C:29]([C:33]([OH:35])=[O:34])([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[F:30][C:29]([F:32])([F:31])[C:33]([OH:35])=[O:34].[Cl:27][C:17]1[C:16]2[C:21](=[CH:22][C:13]([S:10]([NH:9][CH2:8][C:7]([OH:28])=[O:6])(=[O:11])=[O:12])=[CH:14][CH:15]=2)[C:20]([NH:23][C:24]([NH2:26])=[NH:25])=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NCC(=O)O)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine t-butyl ester hydrochloride (50 mg, 0.11 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 1.5 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was triturated with Et2O and EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine trifluoroacetate (36 mg, 0.073 mmol) as a white powder.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]3[CH2:11][CH2:12][O:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:17]([O:19]C)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([C:7]2[C:15]([CH2:17][OH:19])=[CH:14][C:10]3[CH2:11][CH2:12][O:13][C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(Cl)Cl
Reactant: c1cc2c(cc1C1CCCCC1)OCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: OCc1cc2c(cc1C1CCCCC1)OCC2

Procedure:
5 g of 6-Cyclohexyl-2,3-dihydro-benzofuran are dissolved in methylene chloride. 9.5 ml of TiCl4 are slowly added dropwise whilst cooling and stirring, followed by 2.9 g of dichloromethylmethylether in 10 ml of Ch2Cl2. The mixture is stirred for 5 hours at 22°, poured onto ice-water and extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4 and reduced in volume. The residue is dissolved in tetrahydrofuran without further purification. An excess of NaBH4 is added and the mixture refluxed for 3 hours. Natural working of the mixture yields 6-cyclohexyl-2,3-dihydro-5-hydroxymethyl-benzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=O)=[C:5]2[OH:19].[C:20]([NH:33][NH2:34])(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:34][NH:33][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:16])=[C:5]2[OH:19]
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O
Reactant: CCCCCCCCCCCC(=O)NN
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O

Procedure:
Reagents: Comp 35 (0.36 mmols, 0.12 g); dodecanoyl hydrazine (0.4 mmols, 0.08 g). Yield: 0.1 g (55%), white solid, m.p.=160° C.-161° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][C:35]([OH:37])=O>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:35](=[O:37])[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cc2ccccn2)c1

Procedure:
[5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and 2-pyridylacetic acid hydrochloride were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(2-pyridin-2-yl-acetyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 30, Step 2.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[C:11](/[N:13]([CH3:15])C)\[CH3:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[CH:16]1(N)[CH2:20]C[CH2:18][CH2:17]1>CC(O)=O.O>[C:1]([NH:4]/[C:5](=[C:11](/[NH:13][CH:15]1[CH2:18][CH2:17][CH2:16][CH2:20]1)\[CH3:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(NC(C)=O)=C(/C)N(C)C
Reactant: NC1CCCC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)/C(NC(C)=O)=C(/C)NC1CCCC1

Procedure:
(E)-ethyl 2-acetamido-3-(dimethylamino)but-2-enoate (compound 16, 1 g, 4.67 mmol) and cyclopentylamine (0.5 mL) were stirred at room temperature in AcOH (10 mL) for overnight. The reaction mixture was diluted slowly with water (10 mL) and evaporated under reduced pressure to obtain the desired product as a dark brown oil, which could be used without any further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[CH:21]=[C:22]([CH:25]=[O:26])[NH:23][CH:24]=1>>[CH3:1][C:2]1[C:3]([C:20]2[CH:21]=[C:22]([CH:25]=[O:26])[NH:23][CH:24]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: O=Cc1cc(Br)c[nH]1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Product: Cc1cc2c(cc1-c1c[nH]c(C=O)c1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(b), by reaction of 2.47 g (10 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 1.5 g (8.4 mmol) of 4-bromo-2-pyrrolecarboxaldehyde, 950 mg (38.5%) of the expected aldehyde are obtained, with a melting point of 128-9° C.