Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][C:31](O)([CH:33]=[CH2:34])[CH3:32]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:31]([CH3:32])([CH3:30])[CH:33]=[CH2:34])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: C=CC(C)(C)O
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using the procedure of Step A of Example 15, 2 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-carboxy-ethynyl]-cyclopropane-carboxylate, 3 ml of 2-methyl-3-buten-2-ol and 150 mg of 4-dimethylamino-pyridine were admixed at 0° C. with 1.06 g of dicyclohexycarbodiimide in 3 ml of methylene chloride and the mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 700 mg of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-(1,1-dimethylallyloxycarbonyl)-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([O:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([F:30])[CH:8]=1)(=[O:5])=[O:4].C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:35])C>C(O)(=O)C.C(OC(=O)C)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:2]([F:1])([F:31])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:35])[C:10]([C:13]2[N:14]=[N:15][C:16]([O:19][CH:20]3[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:28])([CH3:29])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([F:30])[CH:8]=1)(=[O:4])=[O:5]
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: CC1(C)CC(Oc2ccc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3F)nn2)CC(C)(C)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC(Oc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3F)nn2)CC(C)(C)N1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate (0.48 g, 1.01 mmol), PhI(OAc)2 (0.46 g, 1.41 mmol), and Pd(OAc)2(68 mg, 0.10 mmol) were dissolved in a mixture of acetic acid (4 mL) and acetic anhydride (4 mL). The mixture was stirred at 80° C. for 3 h. The crude reaction was purified by catch and release using SiliaBond Propylsulfonic Acid® (5 eq, CH3CN as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and 3-fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate was afforded as a green solid (0.50 g, 100%). [M+H]: 494.3; 1H NMR (400 MHz, MeOD) δ 8.09 (t, J=8.5 Hz, 1H), 7.99 (dd, J=9.5, 2.5 Hz, 1H), 7.50 (dd, J=10.5, 2.5 Hz, 1H), 7.45 (dd, J=8.5, 2.5 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 5.82 (tt, J=11.0, 4.0 Hz, 1H), 2.24 (dd, J=12.5, 4.0 Hz, 2H), 1.43 (t, J=12.0 Hz, 2H), 1.36 (s, 6H), 1.25 (s, 6H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]#[N:12].[H-].[Na+].CCCCCC.C(OCC)(=O)C.[Cl-].[Na+]>CN(C)C=O>[C:11]([CH:10]1[CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[CH:8][CH:7]=[C:6]12)#[N:12]
Reactant: N#CCc1cccn1CCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC1CCCn2cccc21
Reaction time: 1 h

Procedure:
1-(3-Iodopropyl)pyrrol-2-acetonitrile (31 g., 0.128 moles) is dissolved in dry dimethylformanide (35 ml.) is added with stirring to a cooled (-5°) suspension of sodium hydride (50%, 7.5 g., 0.156 moles) in dry dimethylformamide (100 ml.), maintained in an atmosphere of dry nitrogen, at a rate such that the reaction temperature is maintained between -5° to +5°. When the addition is completed, stirring at this temperature is continued for 1 hour at which time the starting material is shown to be absent by t.l.c. (silica gel, hexane-ethyl acetate, 1:1). A cold, dilute solution of sodium chloride (150 ml.) is added to the reaction during 15 minutes and the product is extracted into benzene. The extract is washed with dilute sodium chloride solution (3 times), with water (once) and then it is dried over sodium sulfate. The solvent is removed in vacuo leaving an oil (21.1 g.) which is chromatographed on silica gel. The crystalline product (13.6 g., 72%) is eluted with hexane-ethyl acetate (97.5:25 and 95:5). Crystallization from hexane-acetone yields 8-cyano-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine (XIX, n is 1), m.p. 47°-49°.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][SH:3].Cl.[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:6]1([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:3][CH2:2][CH2:1][NH2:4])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 103.1 %

Procedure:
Dissolve 2-thioethylamine hydrochloride (5 g, 44.2 mmol), triphenylmethanol (11 g, 42.5 mmol) and triethylamine (7 mL, 49.9 mmol) in 100 mL chloroform. Heat and reflux until the solution temperature reaches a certain temperature, slowly drop a catalyst borontrifluoride ethyl ether complex (15 mL, 119.5 mmol) into the solution and continue heating and reflux for 4 hours. Then cool down, add sodium bicarbonate aqueous solution into the solution and stir the mixture. White solid product is precipitated out immediately. Get the solid by suction filtration, wash the solid with water, and dry the solid. Thus solid product 2-[(triphenylmethyl)thio]ethylamine (14.0 g, 99%) is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](/[Br:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14]C(C)(C)C)=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](/[Br:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 0 °C
Yield: 99 %

Procedure:
A solution of 3.4 g of the product of Step A, 30 ml of toluene, 0.35 g of p-toluene sulfonic acid monohydrate was refluxed until gas evolution ceased and was then cooled to 0° C. and was filtered. The filter was washed with cold toluene and the filtrate was evaporated to dryness at 40° C. under reduced pressure to obtain 2.8 g of (1R,cis) 2,2-dimethyl-3(E)-[2-bromo-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.CCN(C(C)C)C(C)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>C(Cl)Cl>[S:1]1[C:5]([CH2:6][CH2:7][O:8][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OCCc1cc2ccccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 2-benzo[b]thiophen-2-yl-ethanol (16.8 mmol) in CH2Cl2 (60 mL) were added DIPEA (33.6 mmol) and mesylchloride (20.2 mmol.) The mixture was stirred for 18 hrs at RT, diluted with CH2Cl2, washed with sat. NaHCO3 (3×), brine (1×), dried (MgSO4) and concentrated in vacuo to give 4.3 g (99%) of methanesulfonic acid 2-benzo[b]thiophen-2-yl-ethyl ester which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([O:16]CC)=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(O)C>[Cl:1][C:2]1[C:3]([C:14]([NH:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1Cl
Solvent: CCO
Product: O=C(NC1CCOCC1)c1noc(-c2ccc(Cl)cc2)c1Cl

Procedure:
A mixture of ethyl 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylate (20 mg, 0.07 mmol) and 4-aminotetrahydropyran (83 μL, 0.7 mmol) in absolute ethanol (1 mL) was heated to reflux for 36 hours. The volatiles were removed in vacuo and the resulting residue was purified by silica gel chromatography, eluting with dichloromethane, to afford the title compound: (16.8 mg, 0.05 mmol).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH3:2].Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>O>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)=[C:5]([CH:10]=1)[CH2:4][N:3]([C:18]1[N:23]=[N:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1)[CH2:1][CH3:2]
Reactant: CCNCc1cc(Cl)ccc1OCC1CC1
Reactant: NC(=O)c1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN(Cc1cc(Cl)ccc1OCC1CC1)c1ccc(C(N)=O)nn1
Yield: 57.2 %

Procedure:
A mixture of N-ethyl-5-chloro-2-(cyclopropylmethoxy)benzylamine (reference example 20) (4.4 g, 18.4 mmol), 6-chloropyridazine-3-carboxamide (3.0 g 19 mmol), di-isopropylethylamine (5.0 ml, 29 mmol) and DMF (25 ml) was stirred at reflux for 16 hours. The mixture was cooled and diluted with water (50 ml), the gum was allowed to settle out and the supernatant liquor decanted. The gum was dissolved in dichloromethane and stirred while adding 2N hydrochloric acid (50 ml). A precipitate formed after 10 minutes. The solid was filtered off and washed with dichloromethane (10 ml) and ether (20 ml) to give a buff solid (3.8 g, 61%) m.p. 177-8° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][C:31]=3[F:39])[CH:21]=2)=[N:16][CH:15]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=[O:3])[CH3:2].[Cl-].[NH4+].O>C(O)C.[Fe]>[C:1]([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=3[F:39])[CH:21]=2)=[N:16][CH:15]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C)C(=O)COC(C)=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)COC(C)=O
Yield: 46.8 %

Procedure:
The reaction mixture consisting of 206 (300 mg, 0.538 mmol), ammonium chloride (24.75 mg, 0.463 mmol) and iron powder (255 mg, 4.57 mmol) in ethanol (6 mL)/water (3.0 mL) was heated to reflux for 1 h. The reaction mixture was filtered while hot and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-20%, SNAP 25 g cartridge) to give the title compound 207 (133 mg, 0.252 mmol, 47% yield) as a white solid. MS: 528 (MH)+.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][OH:12])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.O[C:14]1[CH:36]=[CH:35][C:17]2[CH2:18][CH:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:22][C:16]=2[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N:1]1[C:2]([CH2:10][CH2:11][O:12][C:14]2[CH:36]=[CH:35][C:17]3[CH2:18][CH:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:26])([F:27])[F:25])[CH2:22][C:16]=3[CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: OCCc1cn2cccnc2n1
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2CN(CC(F)(F)F)C1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1Cc2ccc(OCCc3cn4cccnc4n3)cc2CN(CC(F)(F)F)C1=O

Procedure:
To 55 mL of a tetrahydrofuran solution containing 0.39 g (2.40 mmol) of 2-(imidazo[1,2-a]pyrimidin-2-yl)ethanol obtained in Example 1-(b) were added 0.69 g (2.00 mmol) of ethyl 8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate (see WO 98/14192 A) and 0.74 g (2.80 mmol) of triphenyl-phosphine, and the mixture was stirred under ice-cooling. Then, 2.6 mL of a tetra-hydrofuran solution containing 0.53 g (2.60 mmol) of diisopropyl azodicarboxylate was added dropwise to the mixture over 3 minutes, the mixture was gradually elevated to room temperature, and stirred for 14 hours.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C@H:6]([OH:8])[CH3:7].CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:7][C@@H:6]([O:8][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: CC(C)=CCC[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC[C@@H](C)OS(C)(=O)=O
Temperature: 5 °C
Yield: 88.8 %

Procedure:
(R)-6-Methyl-hept-5-en-2-ol (1) (2.26 g, 17.6 mmol) and DIEA (5.52 mL, 31.7 mmol) were dissolved in anhydrous DCM (24 mL), the reaction mixture was cooled to 5° C., mesyl chloride (1.64 mL, 21.1 mmol) was added dropwise, and the reaction mixture was allowed to slowly warm to RT. After 18 h at RT the reaction mixture was diluted with DCM (60 mL), washed with water (3×35 mL), brine (35 mL), dried with MgSO4, solvent was concentrated to give a dark oil which was purified by SiO2 flash chromatography using Hexane-EtOAc to give the title compound as an oil (3.225 g, 86%). H1 NMR: see supporting information. TLC, Hexane-DCM-EtOAc, 40:40:20, 2 Rf 0.70 (developed with KMnO4 stain). 1H NNMR in CDCl3 (500 MHz): 5.08 ppm 1 Hm, 4.80 ppm 1 Hm, 2.99 ppm 3 Hs, 2.08 ppm 2 Hm, 1.75 ppm 1 Hm, 1.69 ppm 3 Hs, 1.624 1 Hm, 1.61 3 Hs, 1.43 ppm 3 Hd.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[I-].[K+]>O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[N:3][C:2]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)nn2)CC1
Temperature: 150 °C
Yield: 84.6 %

Procedure:
A mixture of 3-chloro-6-trifluoromethyl-pyridazine (4.4 g, 24.1 mmol) (prepared by a procedure similar to that described in Tetrahedron, 1999, 55 (52), 15067-15070), 4-amino-1-tert-butyloxycarbonylpiperidine (9.63 g, 48.1 mmol) and potassium iodide (cat.) were heated in a melt at 150° C. for 30 min. After this period, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, dried and the solvent evaporated in vacuo. The crude product was purified by chromatography (silica; 1%-4% ammonia in methanol (7 M)/dichloromethane) to give D1 (7.06 g, 85%). C15H21F3N4O2 requires 346; Found 347 (MH+)
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[NH:21][CH2:22][CH2:23][CH2:24]O)[CH:9]=[CH:10][CH:11]=1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[NH:21][CH2:22][CH2:23][CH2:24][Cl:3])[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCNC1=Nc2ccccc2C1(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: OC1(c2cccc(Cl)c2)C(NCCCCl)=Nc2ccccc21

Procedure:
Thionylchloride (2.2 g., 1.36 ml.) was added dropwise to a stirred suspension of 3-(m-chlorophenyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol (3.16 g.) in chloroform (25ml.) at 0°C. The reaction mixture was heated under reflux for 45 minutes. the mixture was then cooled and the chloroform evaporated off at reduced pressure. Toluene (25 ml.) was added to the residue and after evaporation the procedure was repeated with a second quantity of toluene. The residue was then dissolved in the minimum quantity of isopropyl alcohol and a small quantity of ether was added to give the title compound as the hydrochloride, colourless rhombs (2.20 g.), m.p. 199° to 203°C.(decomp.). (Found C, 55.15; H, 4.6; N, 7.5. C17H16N2Cl2O2HCl requires C, 54.9; H, 4.6; N, 7.5%)
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[O:17][CH2:18][C:19]([OH:21])=[O:20])=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)Nc1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(NC(=N)N)sc1C(=O)Nc1cccc(OCC(=O)O)c1
Yield: 82.5 %

Procedure:
142 mg of tert-butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate is stirred in 1.1 ml of methylene chloride and 1.1 ml of trifluoroacetic acid (TFA) for 2 hrs. at RT. The reaction mixture is evaporated in a vacuum, the residue is taken up in water and the solution is evaporated to dryness. The solid is suspended in water, adjusted to pH 8 with 1N ammonia while stirring, filtered off under suction, washed with water and dried. There are obtained 101 mg of [3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy]-acetic acid, m.p. 284° C., MS: 350 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[C:14]([C:17]([OH:19])=O)[NH:15][CH:16]=2)=[CH:4][C:5]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([C@H:48]([NH2:51])[CH2:49][OH:50])[CH:42]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:47][C:45]1[CH:44]=[C:43]([CH:48]([NH:51][C:17]([C:14]2[NH:15][CH:16]=[C:12]([C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][CH:9]([CH3:10])[CH3:11])[CH:4]=3)[CH:13]=2)=[O:19])[CH2:49][OH:50])[CH:42]=[CH:41][CH:46]=1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Reactant: CC(C)Nc1cc(-c2c[nH]c(C(=O)O)c2)c(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1cc(-c2c[nH]c(C(=O)NC(CO)c3cccc(Cl)c3)c2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a suspension of 4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid (1.93 g, 6.9 mmol, 1.0 equivalent) in DMF (5.0 mL) was added EDCI (1.45 g, 7.6 mmol, 1.1 equivalents), HOBt (0.94 g, 6.9 mmol, 1.0 equivalent) and (S)-3-chlorophenylglycynol (1.58 g, 7.6 mmol, 1.1 equivalents). Diisopropylethylamine (2.7 mL) was then added and the resulting mixture was stirred a room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was removed and the crude was adsorbed on silica gel. Purification was effected by flash chromatography on silica, eluting with mixtures of hexanes/acetone (from 80:20 to 60:40) to afford the title compound as white solid (1.9 g, 64%). Rt(min) 4.981 s. FIA MS: 433.1 ES+; 431.2 ES−. 1HNMR (CD3OD) δ 1.31 (d, 6H), 3.85 (m, 3H), 5.15 (t, 1H), 7.01 (s, 1H), 7.25 (m, 3H), 7.4 (s, 1H), 7.45 (s, 1H), 7.7 (s, 1H), 7.95 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([CH3:43])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([CH3:43])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C)c2)CCN3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C)c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 182.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) and isobutylaldehyde (0.46 ml) were dissolved in 1,2-dichloroethane (50 ml), and to the solution, triacetoxy sodium borohydride (0.64 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. To the mixture, isobutylaldehyde (0.46 ml) and triacetoxy sodium borohydride (0.64 g) were further added, and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 8) (0.6 g) as pale yellow amorphous.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>>[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:7]2[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]2)=[O:21])=[CH:15][CH:14]=1
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)N2CC(C)(C)NC(C)(C)CC2=O)cc1

Procedure:
Using the same procedure as described in Example 4, 17 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 14.3 parts of p-tolyl isocyanate were reacted together and afforded a solid material which was recrystallised from petroleum ether (of boiling range 60° to 80°C) to yield 21 parts of 4-p-tolylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one of melting point 126°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of quinoline-3-carbaldehyde (1.00 g, 6.36 mmol) in THF (60 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.24 g, 6.36 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution. After stirring for 15 min at RT, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give quinolin-3-ylmethanol SLA 47074A as a yellow oil (1.06 g, >100%). This oil (1.056 g, 6.6 mmol) was dissolved in dry CH2Cl2 (40 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer before dropwise addition of SOCl2 (9.62 mL, 133.3 mmol). The mixture was stirred for 2 h at RT and concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)quinoline hydrochloride SLA 47074B as a yellow solid (1.20 g, 85% yield).