Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:9]([N:8]([C@@H:16]([C@@H:17]([OH:18])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@H](O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 26 (445 mg, 1.76 mmol) and 1-bromopentadecane (1.28 g, 4.39 mmol), alcohol 80 was obtained as a colorless oil (422 mg, 52% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][CH:28]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:29][OH:30]>>[OH:30][CH2:29][CH:28]([NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26])[CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: NC(CO)C1CCOCC1
Product: N#Cc1ccc2c(c1)cc(C(=O)NC(CO)C1CCOCC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 2-amino-2-(tetrahydropyran-4-yl)ethanol in a manner similar to that described in Example 11.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[NH3:14]>C(Cl)(Cl)Cl>[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])(=[O:3])[NH2:14]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
43.5 g (0.181 mole) of methyl 3-chlorosulfonylthiophene-2-carboxylate (VIII) is dissolved in 450 ml of absolute chloroform; ammonia is passed in at room temperature until the mixture has an alkaline reaction. After stirring the solution for a further 3 hours at room temperature (care being taken to keep the solution alkaline) it is extracted with water and the organic phase is dried and evaporated. The crystalline residue may be recrystallized from ethanol; however, for further reaction digestion with ether is sufficient.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]=[CH:3][CH2:4][CH2:5]1
Reactant: OC1CCCOc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2OCC1
Yield: 93.2 %

Procedure:
800 ml of toluene are poured over 53 g (0.323 mole) of 5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin and, with addition of 3.7 g of p-toluenesulfonic acid monohydrate, the mixture is refluxed with a water trap for 1.5 hours. The cold organic phase is washed with saturated sodium bicarbonate solution, water and sodium chloride solution, and the solvent is evaporated off in vacuo. Kugelrohr distillation at 30°-35° C./0.008 torr results in 44 g of oil. p 1H NMR (60 MHz/CDCl3): δ=7.23-6.70 (m, 4H); δ=6.30 (m, 1H); δ=6.07-5.70 (m, 1H); δ=4.20 (t, J=5 Hz, 2H); δ=2.63 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@:31]([CH2:36][C:37]#[N:38])([OH:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].CCOC(C)=O>CO.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@:31]([CH2:36][C:37]#[N:38])([OH:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@](O)(CC#N)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: N#CC[C@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 2-((1S,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanenitrile, 69b, (0.14 g, 0.26 mmol) in methanol (10 mL) was added sodium methoxide (0.06 g, 0.26 mmol). After stirring at room temperature for 2 minutes, the reaction mixture was diluted into EtOAc and brine. The separated organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10% MeOH/CH2Cl2) to afford 46 mg of desired product: 1H NMR (300.0 MHz, MeOD) δ 8.65 (dd, J=2.8, 9.6 Hz, 1H), 8.19 (s, 1H), 8.14 (dd, J=2.0, 2.5 Hz, 1H), 7.98 (d, J=4.1 Hz, 1H), 4.66 (dd, J=8.0, 15.8 Hz, 1H), 2.64 (s, 2H), 2.20 (d, J=12.6 Hz, 2H), 2.01 (dd, J=3.4, 9.8 Hz, 2H), 1.84-1.75 (m, 1H), 1.63-1.47 (m, 2H), 1.33 (dd, J=3.6, 12.4 Hz, 1H) ppm; LCMS RT=2.31 (M+H) 385.45.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C(O)=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC(OP(OC2C=CC=CC=2)([N:36]=[N+]=[N-])=O)=CC=1>C(#N)C>[C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCN
Reaction time: 16 h
Yield: 31.5 %

Procedure:
Acetonitrile (10 mL) was added to octadecanedioic acid mono-tert-butyl ester (500 mg, 1.3 mmol) and TEA (0.226 mL, 1.6 mmol) was added. Diphenylphosphonic azide (0.37 g, 1.3 mmol) was added in a solution of acetonitrile (1 mL). The mixture was stirred at reflux for 2 h, and at RT for 16 h. The reaction was concentrated under vacuum, and suspended/dissolved in 1:2, AcOEt:heptane (2 mL) and applied to a dry bed of silica (2×4 cm dia). It was eluated with 1:2 AcOEt:heptane (2 mL) and 1:1 AcOEt:heptane (60 mL). The eluate was concentrated to dryness. The residue was partly suspended in THF (2 mL) and 1 N NaOH (2 mL) was added. The turbid solution/suspension was stirred for 1 h at RT. Water (15 mL) was added and this was extracted with AcOEt (2×25 mL), adding some brine to aid separation. The organic phase was washed with sat. NaCl, dried, filtered and conc. to dryness. To the residue was added 20% acetonitrile/water (15 mL), TFA (15-20 ul) and DMSO (1 mL). A filtration of the mixture failed, so the filter and the solution were extracted with DCM (2×60 mL). The organic extracts were concentrated to yield the crude product (0.14 g),
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][CH2:13][CH2:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:22][C:23]=2[OH:25])[N:18]([CH3:34])[CH:17]([CH3:35])[CH2:16]1.C(Cl)(Cl)Cl>C(O)(=O)C>[OH:12][CH2:13][CH2:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[O:9])=[CH:22][C:23]=2[OH:25])[N:18]([CH3:34])[CH:17]([CH3:35])[CH2:16]1
Reactant: CCCCSCCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)CCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Equimolar amounts of m-chloroperbenzoic acid and dl-4-(2-hydroxyethyl)-5-hydroxy-1,2-dimethyl-7-(4-thiaoctyl)-1,2,3,4-tetrahydroquinoline are added to a mixture of chloroform and acetic acid (2:1 v/v) and the mixture stirred at room temperature for one hour. The mixture is washed with water, the organic phase dried (MgSO4) and evaporated to dryness at reduced pressure to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][N:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O.C(Cl)(Cl)Cl.Cl>O>[CH3:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:7][CH:8]=[C:9]([CH3:13])[CH:10]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: Cc1cnc(NCCCN)c(C)c1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(NCCCNc2ncc(Cc3ccc(C)nc3)c(=O)[nH]2)c(C)c1

Procedure:
2-(3-Aminopropylamino)-3,5-dimethylpyridine (0.81 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.04 g) were fused together on an oil bath at 140° C. for 6 hr. On cooling the resulting mixture was equilibrated between chloroform and water (pH adjusted to 5.5 with dil. hydrochloric acid). The pH of the aqueous solution was raised to 6.5 and the product extracted out with chloroform. After drying (MgSO4) and stripping, recrystallisation from ethyl acetate and finally twice from ethanol/water gave 2-[3-(3,5-dimethylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone 2.4H2O, (0.83 g; 49%) m.p. 104°-5° C. (softens ca 90° C.).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([OH:24])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23]>C(Cl)Cl>[CH3:4][S:1]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][OH:24])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCOCCOCCOCCOCCO
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCOCCOCCO
Temperature: 20 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
Mesyl chloride (1.78 mL, 23.0 mmol) was added dropwise to a stirred suspension of hexaethylene glycol (5.42 g, 19.2 mmol) and Ag2O (4.67 g, 20.2 mmol) in dry DCM (50 mL) at 20° C. and the mixture was stirred at 20° C. for 3 days. The mixture was filtered through Celite® and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give 17-hydroxy-3,6,9,12,15-pentaoxaheptadec-1-yl methanesulfonate (3.52 g, 51%) as a colourless oil: 1H NMR (CDCl3) δ 4.36-4.40 (m, 2H, CH2OSO2), 3.76-3.78 (m, 2H, CH2O), 3.70-3.74 (m, 2H, CH2O), 3.64-3.67 (m, 16H, 8×CH2O), 3.59-3.62 (m, 2H, CH2O), 3.09 (s, 3H, SO2CH3), 2.80 (br s, 1H, OH); MS m/z 361.6 (MH+, 100%). A mixture of the mesylate (3.52 g, 9.8 mmol) and NaN3 (1.27 g, 19.5 mmol) in dry DMF (20 mL) was stirred at 110° C. for 2 h. The mixture was cooled to 20° C. and the solvent evaporated. The residue was purified by column chromatography, eluting with 10% MeOH/EtOAc, to give 17-azido-3,6,9,12,15-pentaoxaheptadecan-1-ol (2.98 g, 99%) as a colourless oil: 1H NMR (CDCl3) δ3.71-3.74 (m, 2H, CH2O), 3.65-3.69 (m, 18H, 9×CH2O), 3.59-3.62 (m, 2H, CH2O), 3.39 (br t, J=5.2 Hz, 2H, CH2N3), 2.82 (br s, 1H, OH); MS m/z 308.5 (MH+, 100%). A mixture of azide (2.98 g, 9.7 mmol) and Pd/C (100 mg) in EtOH (50 mL) was stirred under H2 (60 psi) for 1 h. The mixture was filtered through Celite® and washed with EtOH (3×20 mL) and the solvent was evaporated. The crude residue was dissolved in DCM (50 mL) and di-tert-butyl dicarbonate (2.56 g, 11.7 mmol) in DCM (20 mL) was added dropwise and the solution was stirred at 20° C. for 16 h. The solvent was evaporated and residue was purified by column chromatography, eluting with 10% MeOH/EtOAc, to give tert-butyl 17-hydroxy-3,6,9,12,15-pentaoxaheptadec-1-ylcarbamate (2.97 g, 80%) as a colourless oil: 1H NMR (CDCl3) δ 5.17 (br s, 1H, NHCO2), 3.70-3.74 (m, 2H, CH2O), 3.60-3.68 (m, 18H, 9×CH2O), 3.54 (br t, J=5.1 Hz, 2H, CH2O), 3.31 (br q, J=5.1 Hz, 2H, CH2N), 2.81 (br s, 1H, OH), 1.44 [s, 9H, C(CH3)3]; MS m/z 382.5
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][C:9]2=[O:20])[CH2:4][CH2:3]1>C(O)C.[Pd]>[NH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:20])[CH:8]2[CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(C2C(=O)Nc3ccc([N+](=O)[O-])cc32)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(C2C(=O)Nc3ccc(N)cc32)CC1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A solution of compound 2 (0.18 g, 0.654 mmol) in dry ethanol (5 mL) was treated with Pd—C (˜0.02 g) and purged with hydrogen gas. The reaction was stirred at room temperature under hydrogen atm. (balloon pressure) overnight (16 h). The reaction was filtered through celite bed, washed with methanol (3×10 mL). The combined organic layer was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 3 (0.08 g, 50%) as a foam. 1H NMR (DMSO-d6) δ 9.89 (s, 1H), 6.57 (s, 1H), 6.48 (d, 1H, J=8.1 Hz), 6.37 (d, 1H, J=8.1 Hz), 4.64 (s, 2H), 2.78-2.67 (m, 2H), 2.09-2.04 (m, 4H), 1.87-1.70 (m, 3H), 1.61-1.52 (m, 2H), 1.37-1.26 (m, 2H); ESI-MS (m/z, %): 246 (MH+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[O:16])[CH2:4][O:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:4][O:3]1
Reactant: OB(O)c1cccnc1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccc(I)cc2)[C@H](c2ccccc2)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCO
Product: CC1(C)OC[C@H](NC(=O)Nc2ccc(-c3cccnc3)cc2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
To a stirred solution of 10 mg (0.0088 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (2.0 mL) was added 100 mg (0.22 mmol) of the product from Example 7. After stirring for 15 min, 27 mg (0.22 mmol) of pyridine-3-boronic acid dissolved in ethanol (0.20 mL) was added followed by 0.22 mL (0.44 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated to 80° C. for 12 h and then cooled to room temperature. The mixture was taken up in 10 mL of dichloromethane and washed with water. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (hexanes/ethyl acetate) to yield 40 mg (45%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)Cc1ccc(-c2cccc(Cl)c2)nc1
Temperature: 67.5 °C

Procedure:
2-chloropyridine-5-acetic acid (0.2 gm, 1.21 mmole), 3-chlorophenylboronic acid (0.2 gm, 1.3 mmole) and 50% water wet 10% Palladium carbon (0.08 gm, 0.036 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.15 gm, 1.4 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst was washed with 20 ml×3 using the above mixture, the filtrate was dried under vacuum and crude mixture was used without any purification in the next step.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C:10](=[O:11])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[F:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:2]([O:5][C:6]([N:8]1[CH2:9][C:10](=[O:11])[CH2:12][C@H:13]1[C:14]([N:21]1[CH2:22][CH2:23][C@H:19]([F:18])[CH2:20]1)=[O:16])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: F[C@H]1CCNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
N-tert-Boc-4-oxo-L-proline (2.29 g, 10 mmol), (S)-3-fluoropyrrolidine hydrochloride (1.38 g, 11 mmol) and TEA (2.09 mL, 15 mmol) were mixed in anhydrous methylene chloride (30 mL) under nitrogen. HOBT (2.03 g, 15 mmol) was added and the mixture cooled to 0° C. in an ice bath before addition of EDC (2.10, 11 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. The mixture was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. The crude material (3.15 g) was recrystallized from hexane:EtOAc (2:1) to give the title compound as light yellow needles (2.18 g, 73%). MS m/z 301.3 (MH+).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])[CH3:2].[ClH:16].[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][C:25](=[O:28])[CH:24]=[CH:23]2>>[ClH:16].[O:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17][C:4]([N:3]([CH2:1][CH3:2])[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[NH:5])[CH:23]=[CH:24][C:25]1=[O:28]
Reactant: Nc1cccc2ccc(=O)oc12
Reactant: CCN(C#N)c1cccc2ccccc12
Agent: Cl
Product: CCN(C(=N)Nc1cccc2ccc(=O)oc12)c1cccc2ccccc12
Reaction time: 9 h

Procedure:
In a 5 ml round bottom flask was placed N-ethyl-N-1-naphthylcyanamide (766 mg, 3.91 mmol), 8-aminocoumarin hydrochloride (818 mg, 4.15 mmol; Clayton, J., Chem.Soc. 97: 1350 (1910)) and a stir bar. The flask was evacuated via aspirator and flushed with N2. This was immediately placed in a preheated 160° C. oil bath where it was allowed to stir under N2 for 9 h. The resulting greenish brown melt was dissolved in methanol (5 ml) and diluted with hot distilled water (20 ml). This solution was basified with 0.1N NaOH (10 ml) and extracted with CHCl3 (4×15 ml) to yield a yellowish brown oil upon drying (910 mg). A TLC of this oil showed a mixture of reactants and product. Reactants were eluted by column chromatography with benzene. The product was eluted with benzene/ethanol 8:1 (TLC Rf =0.44, CHCl3 :EtOH, 1:1), 0.64 g (46%). This pale yellow oil was dissolved in methanol (5 ml), then methanol (5 ml) saturated with HCl gas was added dropwise to yield a light tan foam of the HCl salt after drying. This tan foam was dissolved into ethanol (1 ml) and placed in an ether diffusion chamber for 5 days to afford white prisms, 0.28 g (29%), m.p. 193°-194° C. IR (KBr) 3343, 3303 (--NH), 1712 (carbonyl), 1653 (--C=NH). 1H-NMR (CD3OC) δ 1.12 (t, 3H, J=7.2), 3.55 (q, 2H, J=7.2), 6.47 (d, 1H, J=9.3), 7.30-8.12 (m, 11H, H-aromat and one olefinic). 13C-NMR (CD3OD) CO, 161.4; CN3, 157.6; Ar, 145.7, 136.6, 136.1, 132.5, 131.7, 131.5, 131.16, 130.12, 130.0, 129.5, 129.4, 129.4, 127.3, 126.2, 124.1, 123.2, 121.9, 117.8; CH2, 58.4; CH3, 18.5. Mass Spec. m/e calcd for C22H19N3O2, 357.1477; Found, 357.1453.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[C:15](O)=[O:16])=[O:12])=[CH:9][CH:8]=1.[NH2:33][CH2:34][CH2:35][OH:36]>>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=2)[C:15]([NH:33][CH2:34][CH2:35][OH:36])=[O:16])=[O:12])=[CH:30][CH:31]=1
Reactant: NCCO
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCC2CC2(F)F)cc1
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCC2CC2(F)F)cc1
Yield: 63.1 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-({4-[(2,2-difluorocyclopropyl)methoxy]benzoyl}amino)-3-[4-(trifluoromethoxy)phenyl]propanoic acid (352 mg, 0.766 mmol) prepared in Example 40 (40c) and 2-aminoethanol (55 μL, 0.919 mmol) to give 243 mg of the title compound (white powder, yield: 63%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:19])[O:18][C:7]2=[CH:8][C:9]3[CH2:10][C:11](=[O:17])[N:12]([CH2:15][CH3:16])[C:13]=3[CH:14]=[C:6]2[CH2:5]1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23].Cl>C(Cl)Cl.C1C=CC=CC=1>[CH3:19][C:4]1([CH3:3])[O:18][C:7]2=[CH:8][C:9]3[CH:10]([C:20]([O:21][CH2:22][CH3:23])=[O:24])[C:11](=[O:17])[N:12]([CH2:15][CH3:16])[C:13]=3[CH:14]=[C:6]2[CH2:5]1
Reactant: CCN1C(=O)Cc2cc3c(cc21)CC(C)(C)O3
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)C1C(=O)N(CC)c2cc3c(cc21)OC(C)(C)C3
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a slurry of 26.4 mg. (1.1 mmoles) of sodium hydride in 2 ml. of benzene was added 231 mg. (1 mmole) of 2,2-dimethyl-5-ethyl-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole and the resultant reaction mixture stirred for 5 minutes. To the reaction mixture was added 0.13 ml. (1.1 mmoles) of diethyl carbonate, and the mixture allowed to stir 18 hours. The reaction is then added to methylene chloride and 4N hydrochloric acid, and the organic phase separated, washed with water and a saturated brine solution and dried over magnesium sulfate. The extract was subsequently treated with 1N sodium hydroxide solution and the basic layer separated. The aqueous basic layer was acidified and the product extracted with methylene chloride. The organic phase was separated, dried with magnesium sulfate and concentrated to give 155 mg. (51% yield) of the titled intermediate as an oil.
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:18])[CH2:5][CH2:6][S:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH2:17])=[NH:16])[S:12][CH:13]=1)#[N:2].Cl.CC[O:22]CC>C(O)C.C(Cl)(Cl)Cl>[C:1]([NH:3][C:4](=[NH:18])[CH2:5][CH2:6][S:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH2:17])=[NH:16])[S:12][CH:13]=1)(=[O:22])[NH2:2]
Reactant: N#CNC(=N)CCSCc1csc(NC(=N)N)n1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N=C(N)Nc1nc(CSCCC(=N)NC(N)=O)cs1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a mixture of 15 ml of ethanol and 10 ml of chloroform was dissolved 0.5 g of N-cyano-3-[(2-guanidinothiazol-4-yl)-methylthio]propionamidine and after passing through the solution a dry hydrogen chloride gas for 1.5 hours under cooling by ice water, the reaction mixture was concentrated under reduced pressure. To the residue was added 10 ml of ethanol, the mixture was concentrated again under reduced pressure. The residue formed was dissolved in a small amount of ethanol and after adding thereto ether and allowing to stand overnight the mixture, the crystals deposited were collected by filtration to provide 0.55 g of N-carbamoyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine.di-hydrochloride. The product shows the following physicochemical properties: