Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][C:6]1[S:7](=[O:21])(=[O:20])[O:8][C:9]2[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.N12CCCN=C1CCCCC2.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:5][C:6]1[S:7](=[O:21])(=[O:20])[O:8][C:9]2[C:15]([S:16]([NH:17][C:3]([NH:2][CH3:1])=[O:4])(=[O:19])=[O:18])=[CH:14][CH:13]=[CH:12][C:10]=2[CH:11]=1
Reactant: CN=C=O
Reactant: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CNC(=O)NS(=O)(=O)c1cccc2c1OS(=O)(=O)C(C)=C2
Reaction time: 2 h

Procedure:
1.15 g of methyl isocyanate are added dropwise at 0° C. to a solution of 5.5 g of 3-methyl-8-sulfamoyl-2,2-dioxo-1,2-benzoxathiine and 3.2 g of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture is stirred for 2 hours at 20°-25° C., then diluted with water, neutralised with 5% sodium carbonate solution and filtered. The filtrate is acidified and 5.4 g of N-(3-methyl-2,2-dioxo-1,2-benzoxathiin-8-yl-sulfonyl)-N'-methylurea precipitate. This precipitate is isolated and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(Cl)Cl.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:22][N:23]=1
Reactant: CSc1nncc(-c2ccc(F)c(Br)c2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnnc(-c3ccccn3)n2)cc1-c1ccccn1
Temperature: 60 °C
Yield: 15.9 %

Procedure:
To a mixture of 5-(3-bromo-4-fluorophenyl)-3-methylsulfanyl-[1,2,4]triazine (0.2 g, 0.67 mmol), cuprous 3-methylsalicylate (0.315 g, 1.5 mmol), 2-(tri-n-butylstannyl)pyridine (0.736 g, 2.2 mmol) and lithium chloride (0.085 g, 2.0 mmol) in dry 1,4-dioxane (8 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.032 mmol) and the mixture heated at 60° C. Fog 24 h. The reaction was allowed to cool to ambient temperature, diluted with DCM (20 ml) and washed with 10% ammonia solution (10 ml). The organic layer was washed with water (40 ml) and the combined organics dried over Mg2SO4, filtered and the solvent removed at reduced pressure. The crude product was purified by preparative thin-layer chromatography on silica gel, eluent 3% methanol in dichloromethane. The solid obtained was triturated with diethyl ether to give 5-[4-fluoro-3-(pyridin-2-yl)phenyl]-3-(pyridin-2-yl)-[1,2,4]triazine as a powdery orange solid (35 mg): δH (400 MHz, CDCl3) 7.39-7.48 (3H, m), 7.51 (1H, m), 7.81-8.00 (3H, m), 8.47 (1H, m), 8.71 (1H, m), 8.80 (1H, m), 8.93 (1H, m), 9.81 (1H, s); m/z (ES+) 330 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH:21](C(OCC)=O)[C:22]([O:24]CC)=[O:23].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(C(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC1(CC=C(C)Cl)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Yield: 58.2 %

Procedure:
Crude diethyl 2-[6,7-dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]malonate (36.9 g, 0.075 mole) was refluxed with stirring in a mixture of ethanol (100 ml), water (100 ml) and sodium hydroxide (15 g) for 2 hours. The reaction mixture was cooled, diluted with water and extracted with hexane. The aqueous layer was acidified with hydrochloric acid and extracted with methylene chloride. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum to obtain 17 g of product which after recrystallization from a mixture of methyl cyclohexane and butyl chloride melted at 111°-114° C. and was shown by HPLC to be a 95% trans, 5% cis mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=1[O:18][CH3:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: CCOC(=O)C(C)C(=O)Nc1ccc(Cl)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(C)C(=O)O)ccc1Cl

Procedure:
Prepared according to Procedure B using ethyl 3-(4-chloro-3-methoxyphenylamino)-2-methyl-3-oxopropanoate (3.7 g, 12.95 mmol) in THF (13.0 mL) to give 3-(4-chloro-3-methoxyphenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=258.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23]C)[CH:8]=[N:7][CH:6]=1)[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[OH:23])[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cncc(C2=C(c3cc(Cl)ccc3OC)CCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cncc(C2=C(c3cc(Cl)ccc3O)CCC2)c1
Temperature: -75 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
5-{2-[5-Chloro-2-(methoxy)-phenyl]-cyclopent-1-enyl}-nicotinic acid ethyl ester (1.500 g, 4.20 mmol) in dry dichloromethane (20 mL) was cooled to −75° C. Boron tribromide, 1M solution in DCM, (40 mL, 40.0 mmol) was added and the reaction mixture stirred at −75° C. for a further hour. The temperature of the reaction was then allowed to rise to −15° C. and kept at −15° C. for a further 2 hours, and was then quenched in ice/water (50 g/50 mL). More dichloromethane (60 mL) was added and the resulting mixture was stirred vigorously for ˜2 hrs. The layers were separated and the organic layer was washed with saturated sodium bicarbonate, dried (magnesium sulphate), filtered and reduced to an oil. The oil was then purified by chromatography to give the title compound (0.800 g, 60%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:9]=2[CH3:20])[CH:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[CH3:20][C:9]1[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[S:12][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:7]=1
Reactant: NCCCO
Reactant: Cc1nc(Nc2cnccn2)sc1-c1ccnc(Cl)c1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccnc(NCCCO)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
[5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (Example 2b, 0.077 g, 0.254 mmol) is suspended in 3-amino-propanol (3 ml) and heated to 150° C. using microwave heating (Prolabo Synthewave™ s402 microwave oven). After 1 hour, the reaction mixture is concentrated in vacuo and diluted with water (50 ml). The aqueous is extracted with ethyl acetate (2×100 ml). The combined organic extract is dried (MgSO4) and concentrated to afford the titled compound which is purified by filtration and recrystallised from dichloromethane.
Reaction SMILES: Cl.[CH:2]([C:4]1[C:5]([O:18]COC)=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)=[O:3].O>O1CCCC1>[CH:2]([C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)=[O:3]
Reactant: COCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C=O)c(O)cc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A 10% aqueous solution of hydrochloric acid was added to 30 ml of a solution of 2.4 g of 3-formyl-5,6,7,8-tetrahydro-2-methoxymethoxy-5,5,8,8-tetramethylnaphthalene in tetrahydrofuran at room temperature. The obtained mixture was stirred at 50° C. for 4 hours, followed by the addition thereto of 30 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to removd the solvent. The residue was purified by silica gel chromatography (developer: 10% diethyl ether/n-hexane) to give 1.8 g of the title compound as a colorless oil.
Reaction SMILES: BrCCCCCCCCCC[O:12]C1C=CC(C(O)=O)=CC=1.C1(C=CC=C(O)C=1)O.[CH2:30]([O:42][C:43]1[CH:59]=[CH:58][C:46]([C:47]([O:49][C:50]2[CH:55]=[CH:54][C:53]([CH:56]=[O:57])=[CH:52][CH:51]=2)=[O:48])=[CH:45][CH:44]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].[O-]Cl=O.[Na+]>>[CH2:30]([O:42][C:43]1[CH:44]=[CH:45][C:46]([C:47]([O:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([OH:12])=[O:57])=[CH:52][CH:51]=2)=[O:48])=[CH:58][CH:59]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Agent: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1

Procedure:
Synthesized as described above for compound 7. Quantities: resorcinol (1.79 g, 16 mmol), 11 (5.52 g, 13 mmol), NaH2PO4·H2O (6.29 g, 40 mmol), NaClO2 (7.03 g, 77 mmol). Yield 5.55 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 0.89 (3 H, t, 3J=6.9 Hz, CH3), 1.17-1.71 (18 H, m, CH2), 1.83 (2 H, m, O—CH2—CH2), 4.05 (2 H, t, 3J=6.6 Hz, O—CH2), 6.99 (2 H, d, 3J=8.9 Hz, Ar—H), 7.35 (2 H, d, 3J=8.6 Hz, Ar—H), 8.14 (2 H, d, 3J=8.9 Hz, Ar—H), 8.17 (2 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 300 MHz): 14.1, 22.7, 26.0, 29.1, 29.3, 29.5, 29.6, 29.6, 29.7, 31.9, 68.4, 114.4, 120.9, 122.0, 126.5, 131.9, 132.4, 155.5, 170.3.
Reaction SMILES: [CH3:1][C:2](=[CH2:12])[CH2:3][O:4][CH2:5][C@@H:6]([NH2:11])[CH2:7][CH:8]([CH3:10])[CH3:9].[H][H].Cl>C(O)C.[Pd]>[CH2:3]([O:4][CH2:5][C@@H:6]([NH2:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]([CH3:12])[CH3:1]
Reactant: C=C(C)COC[C@@H](N)CC(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)COC[C@@H](N)CC(C)C
Yield: 93.5 %

Procedure:
A suspension of (1S)-1-(2-methyl-2-propenoxymethyl)-3-methylbutylamine (51.9 g, 0.3 mol) and 5% Pd/C (10.4 g) in ethanol (520 mL) was stirred for 18 hours at room temperature in a hydrogen atmosphere (1 atm.). To the resulting reaction mixture was added 6 mol/L aqueous hydrochloric acid (52 mL) under cooling in ice bath. The aqueous mixture was subjected to filtration using celite for removing insolubles and then placed under reduced pressure for distilling the solvent off. The residue was dissolved in water, and the resulting aqueous solution was made to approx. pH 10 by addition of potassium carbonate. The solution was subjected to extraction with diethyl ether. The organic portion was dried over sodium sulfate and placed under reduced pressure for distilling off the solvent. There was obtained the titled compound (48.6 g, 92.6%) as an oily compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:10]([NH:16][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: Cc1ccc(C)c(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCNc1cc(C)ccc1C
Yield: 84.3 %

Procedure:
According to the general procedure B, 2-Chloro-p-xylene (73 mg, 0.52 mmol) reacted with n-hexylamine (62 mg, 0.61 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (60 mg, 0.63 mmol) in toluene at 100° C. for 10 h to give the title compound (90 mg, 87%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.00 (d, 1H, J=7.2 Hz), 6.54 (d, 1H, J=7.6 Hz), 6.51 (s, 1H), 3.45 (bs, 1H), 3.20 (dd, 2H, J=6.8 and 7.2 Hz), 2.37 (s, 3H), 2.16 (s, 3H), 1.73 (m, 2H), 1.49 (m, 2H), 1.41 (m, 4H), 0.99 (t, 1H, J=6.8 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.23, 136.65, 129.77, 118.61, 117.14, 110.46, 43.92, 31.63, 29.56, 26.90, 22.63, 21.54, 16.98, 14.03. GC/MS(EI): m/z 205 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[F:11][C:12]1[C:21]([I:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:13]=1[C:14](Cl)=[N:15][OH:16].O>O1CCCC1>[F:11][C:12]1[C:21]([I:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:13]=1[C:14](=[N:15][OH:16])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc(C(Cl)=NO)c(F)c1I
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNC(=NO)c2ccc(C)c(I)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
4-Methoxybenzylamine (2.00 mL, 15.2 mmol) was added dropwise to a solution of 2-fluoro-N-hydroxy-3-iodo-4-methylbenzimidoyl chloride (WO2006094187, 1.46 g, 4.7 mmol) in tetrahydrofuran (20 mL) and the mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give a semi-solid. The solid was triturated with a hexanes/diethyl ether mixture and the solid was filtered and dried to give the title compound (1.66 g, 86%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:41]3[CH:42]=[CH:43][CH:44]=[C:45]4[C:50]=3[CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]4)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:8])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(Br)c2C1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c3c2)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cccc5c4CN(C(=O)OC(C)(C)C)CC5)cn(C)c3c2)c(OC)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate H)(0.188 g, 0.330 mmol), tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.257 g, 0.824 mmol), potassium phosphate (0.315 g, 1.483 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.027 g, 0.033 mmol). DMF (2.197 ml) was added, and the vial was flushed with argon, sealed, and stirred at 85° C. for two hours. Additional tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (Oakwood Inc., West Columbia, S.C.) (0.257 g, 0.824 mmol) was added and the reaction was stirred at 85° C. for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g silica gel column (Teledyne Isco, Lincoln, Nebr.), gradient elution 0 to 100% EtOAc:Hex) to afford tert-butyl 8-(6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-methyl-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a light yellow solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:10])[CH2:6][CH2:7][CH2:8][NH2:9]>>[NH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:10][CH2:3][CH2:2][C:1]#[N:4]
Reactant: C=CC#N
Reactant: NCCCCN
Product: N#CCCNCCCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Acrylonitrile (5.08 g, 0.096 mol) was added to ice bath-cooled 1,4-butanediamine (8.44 g, 0.096 mol) in 30 min. The resulting mixture was stirred for 2 h at RT, heated to 50° C. for further 3 h and finally let stirring at RT overnight. After Kugelrohr distillation colourless oil was obtained (5.80 g, 0.041 mol, yield 42.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[N:7]=1.CC(=CC)C.Cl([O-])=[O:19].[Na+]>CC(O)(C)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:19])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cnc2ccc(Cl)nn12
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-3-carbaldehyde (1.82 g, 10 mmol), in t-BuOH (90 mL) and 2-methyl-2-butene in THF (30 mL, 2.0 M) was added a solution of sodium chlorite (80%, 9.0 g, 100 mmol) and NaH2PO4 (1 g, 8 mmol) in water (45 mL). The mixture was stirred at rt for overnight, concentrated, diluted with water, acidified to PH=4, precipitated white solid, filtered to give 6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid as white solid (1.2 g, 67% yield)). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, J=9.60 Hz, 1H), 8.22 (s, 1H), 7.50 (d, J=9.60 Hz, 1H); LRMS (ESI) m/e 198.1 [(M+H)+, calcd for C7H6ClN3O2 198.6].
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OC(C)(C)C)=O)[C@H:10]1[CH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=O)[CH2:2][CH2:3][CH3:4].[CH2:33]([CH:38]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH2:39]1)[CH2:34][CH2:35][CH2:36][CH3:37].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(COCC=C)C1)=O)CCC.C(NC(=O)[C@H](C(C)C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C=CC=CC=2OC(C(NC)=O)C1)=O)CCC.C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C=CC=CC=2OC(C=NOC)C1)=O)CCC>>[CH2:1]([NH:5][C:6](=[O:32])[C@H:7]([CH3:31])[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:23][C:24]([CH3:29])([CH3:30])[CH2:25][C:26]([N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:47][CH:38]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:39]1)=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC1CNc2ccccc2C1
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O
Agent: C=CCOCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1
Agent: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)NC)Oc2ccccc21)NC(=O)OC(C)(C)C)C(C)C
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C=NOC)Oc2ccccc21)NC(=O)OC(C)(C)C
Product: CCCCCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](N)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1

Procedure:
Starting from 230 mg of 3-[N-tert-butoxycarbonyl-4(S)-(3-carboxy-2,2-dimethylpropyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide and 284 mg 3(R,S)-pentyl-1,2,3,4-tetrahydroquinoline via (4O,5N-isopropylidene)-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-pentyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide (analogously to Example 1a); Rf (A)=0.44) and 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-pentyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide (Rf (X)=0.47; FAB-MS: (M+H)+ =602) in a manner analogous to that described in Example 1), as a diastereomer mixture: Rf (V)=0.33; Rt (VI)=30.1 min; FAB-MS: (M+H)+ =502.
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][NH+:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)[CH2:6]1>O.CO>[CH3:4][N:5]1[CH2:10][CH:9]=[CH:8][CH:7]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)[CH2:6]1
Reactant: C[NH+]1CCCC(c2cc3ccccc3o2)C1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC=CC(c2cc3ccccc3o2)C1

Procedure:
A solution of 50 g of sodium borohydride in 100 ml of water is added dropwise, with stirring and external cooling, to a solution of 56.0 g of 1-methyl-3-(2-benzofuranyl)-piperidinium-iodide in 600 ml of methanol, the manner of addition being such that the reaction temperature does not exceed 35°. The solution is subsequently stirred for 15 hours at room temprature and again a solution of 50 g of sodium borohydride in 100 ml of water is added dropwise at a temperature not exceeding 35°. The methanol is thereupon evaporated off in vacuo; the aqueous phase remaining behind is extracted twice with 300 ml of chloroform each time, the chloroform solution dried over sodium sulphate, filtered, and concentrated by evaporation. The 1-methyl-3-(2-benzofuranyl)-1,2,3,6-tetrahydropyridine obtained is recrystallised from di-isopropylether, and then melts at 63°. The hydrochloride prepared therefrom with a solution of hydrogen chloride in ethyl acetate melts, after recrystallisation from ethyl acetate, at 244°-246°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NC1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Cyclohexylamine (2.77 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with water. The solid was collected by filtration, washed with water, and dried under high vacuum over the weekend. The solid was recrystallized from isopropyl alcohol-95% ethanol, collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 3.75 g (73%) of crystals, mp 240°-241° C.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].O=[CH:8][C:9]1[CH:18]=[CH:17][C:15]([OH:16])=[C:11]([O:12][CH2:13][CH3:14])[CH:10]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:13]([O:12][C:11]1[CH:10]=[C:9]([CH:8]=[CH2:1])[CH:18]=[CH:17][C:15]=1[OH:16])[CH3:14]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(O)c(OCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (1.15 mole) and potassium tert-butylate (1.33 moles) in 1 liter toluene was stirred for 1 hour at room temperature. 1.0 mole of ethylvanillin was added to the ylide thus formed. The reaction mixture was stirred for another hour and then washed with dilute hydrochloride acid. The solution was concentrated by evaporation and the residue distilled under reduced pressure. In this way 2-ethoxy-4-vinylphenol was obtained in a yield of 55%. Boiling point: 75° C./15 Pa.