Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:31][OH:32]>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:32][CH2:31][C:30]([O:34][CH2:35][CH3:36])=[O:33])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1
Reactant: CCOC(=O)CO
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Product: CCOC(=O)COc1nc(SC)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (K), is treated with ethyl glycolate, a compound of formula (P), to yield 2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (U).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH:12]([CH3:21])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(#N)C>[CH3:21][C:12]1[N:6]2[C:2]([S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)=[N:1][C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc2ccccc2s1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC#N
Product: Cc1c(-c2ccccc2)nc2sc3ccccc3n12
Yield: 17.3 %

Procedure:
To 50 ml of acetonitrile were added 10 g of 2-aminobenzothiazole and 7 g of α-bromopropiophenone and the mixture was refluxed for 3 days. After cooling the reaction mixture, the precipitated hydrobromide of 2-aminobenzothiazole was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 ml of chloroform and then 100 ml of ethyl acetate was added to the solution. The supernatant formed was recovered and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography and then the product was eluted using chloroform as the eluant to provide 1.5 g of 3-methyl-2-phenylimidazo[2,1-b]benzothiazole.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][N:29]=[C:30]=[O:31]>ClCCl>[CH3:28][NH:29][C:30]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=3[Cl:27])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:31]
Reactant: CN=C=O
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(c4ccccc4)C3)cc2)c1
Solvent: ClCCl
Product: CNC(=O)N1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made in the following manner: 55 mg of 3-phenyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 2 equiv. methylisocyanate would be added. The reaction would be shaken at room temperature overnight. The reaction would be concentrated in vacuo. The residue would be diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo would afford the title compound as hydrochloride salt.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.I[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH3:1][C@@H:2]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)=CCC[C@H](C)CCc1ccc(B(O)O)cc1
Product: CC(C)=CCC[C@H](C)CCc1ccc(-c2ccc(N)cc2)cc1
Yield: 67.4 %

Procedure:
A mixture of 4-[(3S)-3,7-dimethyl-6-octenyl]phenylboronic acid (5.00 g, 19.2 mmol), 4-iodoaniline (2.79 g, 12.75 mmol), and a quaternary ammonium salt (Aliquat 336, 1.3 g) was degased three times with nitrogen before 100 mL of dry toluene was added. This step was followed by addition of tetrakis(triphenylphosphine)palladium (1.46 g) and aqueous sodium carbonate (1 M, 60 mL, deaerated for 2 hours) under nitrogen. The mixture was stirred vigorously and heated under reflux for 20 hours. The organic phase of the resulting reaction mixture was filtered through a thin layer of Celite® and evaporated to dryness to give 3.09 g of crude material. The crude material was purified by chromatography on silica gel (ethyl acetate:hexanes) to yield 4-[(3S)-3,7-dimethyl-6-octenyl]-4′-aminobiphenyl as a yellow oil (2.64 g, 8.59 mmol, 67.4% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[Cl:17]C1C2C(=CC=CC=2)C(O)=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[C:9]([Cl:17])[CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: O=c1cc(O)c2ccc3ccccc3c2o1
Product: O=c1cc(O)c2cc(Cl)c3ccccc3c2o1
Yield: 30 %

Procedure:
The procedure was identical to that used for the preparation of 10a: 30% yield (starting with 4-chloro-1-naphthol 9d); 1H NMR (DMSO) δ 5.90 (1H, s, H-3), 7.81 (2H, m, H-8, 9), 7.90 (1H, s, H-5), 8.25 (1H, d, J=7.8 Hz, H-7), 8.43 (1H, d, J=7.5 Hz, H-10).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 87 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.19-3.33 (m. 4H), 3.72-3.77 (m, 4H), 4.13 (s, 3H), 6.79-7.66 (m, 7H), 7.71 (d, J=8.6 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.C(N(CC)CC)C.C(O)C.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:29]([O:28][C:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)=[O:27])[CH3:30]
Reactant: O=C(O)C1CCc2cc(I)ccc2O1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)CCC(C(=O)O)O2
Temperature: 60 °C
Reaction time: 60 h

Procedure:
A 2-neck round bottom flask fit with a reflux condenser was charged the compound from Example 28 (1.05 g, 3.45 mmol) and palladium (II) acetate (23 mg, 0.10 mmol). The flask was placed under an atmosphere of carbon monoxide (1 atm). Triethylamine (1.20 mL, 8.63 mmol) and absolute ethanol (2.0 mL) were added via syringe. The dark reaction mixture was heated to 60° C. and stirred for 60 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting dark solution was washed sequentially with 7% aqueous hydrochloric acid, water, and saturated aquesous sodium chloride. The organic layer was dried (MgSO4), and concentrated to an orange oil which crystallized on standing to a pale solid (0.675 g, 81%). 1H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.68 (m, 2H), 6.90 (m, 1H), 4.89 (m, 1H), 4.25 (q, J=7.36 Hz, 2H), 2.82 (m, 1H), 2.66 (m, 1H), 1.28 (t, J=6.98 Hz, 3H); MS (CI) m/z 251 (MH+).
Reaction SMILES: BrC1C=CC(C2(NCCC3(O)CCC4(OCC(C)(C)CO4)CC3)CC2)=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Br:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2([N:50]3[CH2:55][CH2:54][C:53]4([CH2:67][CH2:66][C:58]5(OCC(C)(C)C[O:59]5)[CH2:57][CH2:56]4)[O:52][C:51]3=[O:68])[CH2:49][CH2:48]2)=[CH:43][CH:42]=1>>[Br:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2([N:50]3[CH2:55][CH2:54][C:53]4([CH2:67][CH2:66][C:58](=[O:59])[CH2:57][CH2:56]4)[O:52][C:51]3=[O:68])[CH2:49][CH2:48]2)=[CH:43][CH:42]=1
Reactant: CC1(C)COC2(CCC3(CCN(C4(c5ccc(Br)cc5)CC4)C(=O)O3)CC2)OC1
Agent: CC1(C)COC2(CCC(O)(CCNC3(c4ccc(Br)cc4)CC3)CC2)OC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C1CCC2(CC1)CCN(C1(c3ccc(Br)cc3)CC1)C(=O)O2

Procedure:
The title compound is prepared from 9-{2-[1-(4-bromo-phenyl)-cyclopropylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[1-(4-bromo-phenyl)-cyclopropyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 19% of theory; LC (method 7): tR=1.37 min; Mass spectrum (ESI+): m/z=378/380 (Br) [M+H]+.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][OH:30])=[N:20][N:21]=2)[CH:18]=1.CCN(CC)CC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][O:30][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[N:20][N:21]=2)[CH:18]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Triisopropylsilyl chloride (266μ□L, 1.24 mmol) was added to a solution of Intermediate 84e (218 mg, 0.82 mmol) and Et3N (26μ□L, 1.24 mmol) in DCM (8.00 mL). The reaction was stirred overnight then 4-(dimethylamino)pyridine (10.0 mg, 0.082 mmol) added. The reaction was stirred for 3 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% [2M NH3 in MeOH] in DCM, to give the title compound (317 mg, 92%). 1H NMR (300 MHz, CDCl3): 0.92 (21H, s), 1.56-1.68 (2H, m), 1.89-2.10 (3H, m), 2.21-2.40 (3H, m), 2.56 (1H, dt, J 12.1, 7.9), 3.40 (1H, m), 3.46-3.64 (2H, m), 4.22 (1H, t, J 8.4), 7.16 (1H, ddd, J 9.9, 7.5, 2.3), 7.71 (1H, ddd, J 10.0, 4.9, 0.6), 8.64 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)ccn1

Procedure:
A mixture of 4-Chloro-N-[5-chloro-2-(2-methyl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (150 mg, 0.27 mmol) from Example 39 dissolved in 4 M HCl in dioxane (10 mL), and water (4 mL) was heated at 100° C. for 3 h. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH: CH2Cl2: 1:99, then 2:98) to provide the desired product. 1H NMR (400 MHz, CDCl3) δ 10.9 (s, 1 H), 8.64 (d, J=5.2 Hz, 1 H), 8.36 (s, 1 H), 8.18-8.16 (m, 2 H), 7.96 (d, J=8.4 Hz, 1 H), 7.62 (d, J=8.4 Hz, 1 H), 7.41-7.38 (m, 2 H), 2.64 (s, 3 H); MS m/z: 490.0 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][C:23]=3[O:32][CH2:33][O:34][CH3:35])(O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:4]([Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][C:23]=3[O:32][CH2:33][O:34][CH3:35])=[CH:17][CH2:16]2)=[CH:13][CH:14]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COCOc1ccc(C2(O)CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COCOc1ccc(C2=CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Temperature: 25 °C

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-[2,4-bis(methoxymethoxy)phenyl]cyclohexanol (125 mg, 0.25 mmol), toluene (10 ml) and p-toluene sulfonic acid monohydrate (3 crystals). The reaction mixture was heated to reflux temperature for 30 min, then cooled to room temperature before adding saturated aqueous sodium bicarbonate (5 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The title compound was isolated without further purification as an oil (118 mg, 98%) and a mixture of diastereoisomers. δH(CDCl3) 0.19 (6H, s), 0.98 (9H, s), 1.84 (1H, m), 2.00 (1H, m), 2.27 (1H, m), 2.44 (2H, m), 2.56 (1H, m), 3.48 (3H, s), 3.49 (3H, s), 5.15 (2×2H, s), 5.79 (1H, m), 6.67 (1H, dd), 6.77 (2H, d), 6.78 (1H, d), 7.07 (2H, d), 7.11 (1H, d).
Reaction SMILES: FC(F)(F)C(O)=O.C([S:11][CH2:12][CH:13]([CH2:28][CH2:29][CH2:30][NH2:31])[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])(=O)C>O.N>[NH2:31][CH2:30][CH2:29][CH2:28][CH:13]([CH2:12][SH:11])[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15]
Reactant: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)C(CS)CCCN)C(=O)O

Procedure:
Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-arginine trifluoroacetate (2 g) is dissolved in a mixture of water (25 ml) and concentrated ammonia (25 ml) and this solution is stored at room temperature for twenty minutes. The solution is concentrated in vacuo to ca. 5 ml and applied to a column of Dowex 50 ion exchange resin (50 ml) in the hydrogen cycle. After washing with water Nα -(5-amino-2-mercaptomethylpentanoyl)-L-arginine is eluted with a pyridine-acetate buffer at pH 6.5.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:18]O>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:18])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1ccc2ncccc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2ncccc2c1
Temperature: 65 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a solution of quinoline-6-carboxylic acid (183 g, 1.06 mol) in methanol (1 lit.), thionyl chloride (150.7 g, 1.2 mol) was added dropwise at 0° C. and then stirred at 65° C. for 12 h. The reaction mixture was concentrated and to the residue dichloromethane and aqueous sodium carbonate solutions were added. The organic layer was dried with sodium sulphate and concentrated to afford the title compound as a brown solid (150 g, 75%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:1]
Reactant: CS(=O)(=O)Nc1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C=O
Reaction time: 12 h
Yield: 78 %

Procedure:
Manganese dioxide (85%, 45.0 g, 0.52 mol) was added to a solution of N-[2-(hydroxymethyl)phenyl]methanesulfonamide (13.0 g, 65 mmol) in dichloromethane (200 mL) at ambient temperature under nitrogen. The reaction mixture was stirred for 12 h and then filtered through a pad of Celite. The pad was washed with dichloromethane/methanol (1:1) and the combined organics were concentrated to afford N-(2-Formylphenyl)methanesulfonamide (10.1 g, 78% yield) as a yellow solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[C:26]([O:30][C:31]([NH:33][C:34]1[CH:35]=[C:36](O)[CH:37]=[CH:38][CH:39]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:38]3[CH:39]=[C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:35]=[CH:36][CH:37]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: OC1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(OC2CCN(c3ccncc3)CC2)c1
Temperature: 4 °C
Yield: 66.2 %

Procedure:
Diethyl azodicarboxylate (3 ml) was added over 15 minutes to a stirred mixture of 1-(4-pyridyl)piperidin-4-ol (3.39 g), 3-(N-tert-butoxycarbonylamino)phenol (Chemical Abstracts, vol. 119, abstract 139113; PCT Patent Application WO 9306085; 3.98 g), triphenylphosphine (4.99 g) and THF (150 ml) which had been cooled to 4° C. The resultant mixture was stirred for 48 hours at ambient temperature. The solvent was evaporated and the residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. The resultant foam was crystallised from diethyl ether to give tert-butyl N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}carbamate (4.65 g), m.p. 165-166° C.
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)[N:9]=1)[C:2]([NH2:4])=[NH:3].[OH-].[Na+].Cl>O.C(O)C>[NH:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CCCCN2C(=O)c3ccccc3C2=O)c[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1nc(CCCCN)c[nH]1

Procedure:
To a solution of 2-guanidino-4-(4-phthalimidobutyl)imidazole (0.25 g.) in water/ethanol 1:1 v/v (20 ml.) was added sufficient dilute sodium hydroxide solution to give a pH of 12. The mixture was heated under reflux for 30 minutes, the pH adjusted to 3 with concentrated hydrochloric acid, the mixture heated under reflux a further 30 minutes and then cooled. The pH was readjusted to 12 with sodium hydroxide solution and then the total mixture evaporated to dryness to give crude 2-guanidino-4-(4-aminobutyl)imidazole which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]([CH3:23])([CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][NH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH2:15][C:14]([CH3:23])([CH3:13])[CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)(CN)CN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the 4-amino-3-methoxy-benzoic acid (Aldrich; 2 g, 12 mmol) and 2,2-dimethyl-3-pyrrolidin-1-yl-propan-1-amine (WO 2004033419; 2.1 g, 13.2 mmol) were dissolved in DMF (50 mL), and to the solution was added DIPEA (3.1 g, 4.2 mL). The reaction was cooled with an ice-bath, and to it was added, portionwise, HATU (5.02 g, 13.2 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated, and the residue was partitioned between Ethyl Acetate (100 mL), and saturated aqueous sodium carbonate solution (3×40 mL), washed with brine (3×40 mL), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated. The residue was purified by chromatography on a silica column pre-conditioned with Ethyl acetate and eluted with 10% MeOH-DCM+1% NH3. Those fractions containing the desired product were combined and the solvent was evaporated to yield the title compound as a pale brown gum, which crystallised on standing. (500 mgs; 14%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][C@@H:4]1[CH3:19].[H][H]>CO.[Pd]>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[CH3:19]
Reactant: CO[C@H]1CCN(C(=O)OCc2ccccc2)C[C@@H]1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1CCNC[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,4S)-benzyl 4-methoxy-3-methylpiperidine-1-carboxylate (4.0 g, 15.19 mmol) in MeOH (150 mL) under an argon atmosphere was added wet Pd/C [(5% dry basis) (1.617 g, 0.759 mmol)] The atmosphere was replaced with hydrogen gas via a balloon. The heterogeneous mixture was stirred for 1 hour at room temperature, and then filtered through Celite®. The filter cake was washed with dichloromethane (150 mL) followed by 20% MeOH/DCM (150 mL). The eluent was concentrated to afford (3S,4S)-4-methoxy-3-methylpiperidine which was used without the need for further purification. 1H NMR (400 MHz, CD2Cl2) δ ppm 0.91 (d, J=6.6 Hz, 3 H) 1.20 (tdd, J=12.2, 12.2, 10.5, 4.3 Hz, 1 H) 1.37-1.55 (m, 1 H) 2.03 (ddt, J=12.6, 4.2, 3.0, 3.0 Hz, 1 H) 2.21 (dd, J=12.6, 10.6 Hz, 1 H) 2.53 (td, J=12.4, 2.8 Hz, 1 H) 2.70-2.81 (m, 1 H) 2.95 (ddd, J=12.5, 4.3, 1.6 Hz, 1 H) 3.01-3.11 (m, 1 H) 3.31 (s, 3 H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][CH:23]1[CH:27]([CH3:28])OS(=O)(=O)[N:24]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O>CN(C=O)C.CCOC(C)=O>[C:34]([O:33][C:31]([NH:24][CH:23]([CH3:22])[CH:27]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:28])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: CC1OS(=O)(=O)N(C(=O)OC(C)(C)C)C1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 60% NaH dispersion in mineral oil (596 mg, 14.9 mmol) in DMF (14 mL) at 0° C. is added a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 3.9 g, 14.9 mmol) in DMF (14 mL). The mixture is stirred for 40 min, then a solution of tert-butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.8 g, 14.9 mmol) in DMF (7 mL) is added. The reaction mixture is stirred for 30 min at 0° C. and then is warmed to room temperature and stirred for 65 h. Water is added and the mixture is stirred for 15 min before EtOAc (50 mL) is added. Then the organic layer is separated, washed with aqueous NH4Cl solution, water, and brine, dried (MgSO4) and concentrated to afford the crude title compound, which was used directly in the next reaction.