Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([C@@H:10]1[CH2:14][C@@H:13]([C@@H:15]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:16][C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:12][C:11]1=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.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=2SC(C(NCC)=O)C1)=O)CCC>O1CCCC1>[CH3:1][NH:2][C:11](=[O:38])[C@H:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][C@H:13]([OH:12])[C@@H:15]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:16][C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN
Reactant: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Agent: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)NCC)Sc2ccccc21)NC(=O)OC(C)(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccccc1)C[C@H](O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
8 ml of methylamine are passed into a solution of 476 mg of 3(R)-benzyl-5(S)-[5-benzyloxy-1(S)-tert-butoxycarbonylamino-3,3-dimethyl-pentyl]-2-oxotetrahydrofuran (Example 74d)) in 4 ml of tetrahydrofuran at 0° C. and a condensation reaction is carried out. The solution is stirred at room temperature for 30 h and concentrated and the residue is further reacted without chromatography: Rf (L)=0.48; FAB-MS:(M+H)+ =527.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].CN(C=O)C.[CH3:11][O:12][C:13]1[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=1[CH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=1>>[CH3:11][O:12][C:13]1[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=1[CH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccccc1Cc1cc2ccccc2s1
Solvent: CN(C)C=O
Product: COc1ccccc1Cc1sc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with sulfuryl chloride (8.4 mmoles, 0.7 ml), DMF (9.8 mmoles, 0.8 ml) and 2-(2-methoxybenzyl)-benzo[b]thiophene (4.9 mmoles, 1.25 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.94 g (54%) of a yellow solid.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:5]=1[Cl:22]>CO.ClCCl>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:5]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(C=O)cc2)cc(N)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(CO)cc2)cc(N)c1Cl
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
Sodium borohydride (112 mg, 3 mmol) was slowly added to a solution of methyl 4-amino-3-chloro-6-(4-formylphenyl)pyridine-2-carboxylate (2.87 g, 9.87 mmol) in methanol/dichloromethane (1:1, 100 mL) cooled by an ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was stirred for 15 minutes and then concentrated. The residue was dissolved in ethyl acetate/water and the organic phase was washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography over silica gel (40% ethyl acetate/hexane) to yield methyl 4-amino-3-chloro-6-(4-hydroxymethylphenyl)pyridine-2-carboxylate (2.5 g 8.54 mmol), mp 138-139° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+].Cl[CH2:20][CH2:21][CH2:22][P:23](=[O:34])([O:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:24][CH2:25][CH2:26][CH2:27][CH3:28].C(OCC)(=O)C>C(O)C.C(Cl)(Cl)Cl.O>[CH2:1]([O:8][N:9]([CH2:20][CH2:21][CH2:22][P:23](=[O:34])([O:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:10]([O:11][CH2:12][CH3:13])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOP(=O)(CCCCl)OCCCC
Reactant: CCOC(=O)NOCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCOP(=O)(CCCN(OCc1ccccc1)C(=O)OCC)OCCCC
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of ethyl N-benzyloxycarbamate (7.80 g.) in absolute ethanol (5 ml.) was added dropwise to a solution of sodium ethoxide in absolute ethanol [Na: 920 mg., absolute C2H5OH: 100 ml.] at 70° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise dibutyl 3-chloropropylphosphonate (10.8 g.), whereafter the reaction mixture was refluxed with stirring for 22 hours. The resultant mixture was cooled to give precipitates, which were filtered off. The filtrate was concentrated under reduced pressure to give a residue. To the residue was added ethyl acetate (100 ml.) and water (50 ml.). The ethyl acetate layer was separated, dried over magnesium sulfate and then concentrated under reduced pressure to give an oily residue (16.6 g.). The residue was subjected to column chromatography on silica gel with an eluent (chloroform). Fractions containing the object compound were collected and concentrated under reduced pressure to give oily dibutyl 3 -(N-benzyloxy-N-ethoxycarbonylamino)propylphosphonate (7.33 g.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].CC[O:12][C:13]([CH:15]([C:17]([C:19]([O:21]CC)=[O:20])=O)[CH3:16])=O.C(OCC)C>O>[C:19]([C@H:17]1[C@@H:15]([CH3:16])[C:13](=[O:12])[C:6]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:8][C:7]=2[CH3:9])[NH:5]1)([OH:21])=[O:20]
Reactant: Cc1cc(C)cc(N)c1
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C)c2c(c1)N[C@@H](C(=O)O)[C@@H](C)C2=O

Procedure:
These compounds were prepared by the route outlined in Example 1 using 3,5-dimethyl aniline and diethyloxalpropionate as the starting materials in the first step. The cis and the trans isomers were distinguished by X-ray crystallography. Trans isomer (Example 3) [m.p. 156°-157° C. (diethyl ether)]; δ (360 MHz, CDCl3), 1.35 (3H, d, J=7.2 Hz, CH3CHBCHA), 2.23 (3H, s, CH3Ar), 2.54 (3H, s, CH3Ar), 2.97 (1H, m, CH3CHBCHA), 3.97 (1H, d, J=4.9 Hz, CH3CHACHB), 6.40 (2H, s, 6-H and 8-H); m/e 233 (M+), 188 (100%, -CO2H); Found: C, 66.73; H, 6.50; N, 5.95. C13H15NO3 requires C, 66.94; H, 6.48; N. 6.00%. Cis-isomer (Example 4) (oil); δ (250 MHz, CDCl3) 1.17 (3H, d, J=7.2 Hz, CH3CHBCHA). 2.24 (3H, s, CH3Ar), 2.57 (3H, s, CH3Ar), 2.95 (1H, dq, J=7.2 and 4.0 Hz, CH3CHBCHA), 4.43 (1H, d, J=4.0 Hz, CH3CHBCHA), 4.90 (1H, br, s, NH), 6.40 (1H, s, 6-H or 8-H), 6.42 (1H, s, 6-H or 8-H); m/e 233 (M+), 188 (100%, M-CO2H); Found: C, 64.97; H, 6.53; N, 5.72. C13H15NO3.0.4 H2O requires C, 64.93; H, 6.62; N, 5.82%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:34]1([O:33][C:31]([N:26]2[CH2:27][CH2:28][CH:23]([NH:22][C:20]([NH:19][CH2:18][C:7]3[C:6](=[O:29])[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:8]=3)=[O:21])[CH2:24][CH2:25]2)=[O:32])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 20 mL round-bottomed flask, 1-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)-3-(piperidin-4-yl)urea (intermediate N) (0.100 g, 0.243 mmol), phenyl chloroformate (38.1 mg, 30.6 μL, 0.243 mmol) and N,N-diisopropylethylamine (157 mg, 213 μL, 1.22 mmol) were combined with CH2Cl2 (5 ml). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated. The crude product was purified using preparative reverse-phase HPLC to give 4-[3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-piperidine-1-carboxylic acid phenyl ester. MS calcd. for C29H28ClN4O4 [(M+H)+] 531.2, obsd. 531.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1
Reactant: [H][H]
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ncnn1-c1ccc(N)cc1F
Yield: 75.2 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-5-methyl-1H-[1,2,4]triazole (120 mg, 0.54 mmol) was dissolved in tetrahydrofurane (6 mL) and triethylamine (10 mL) and stirred for 4 hours with 10% palladium on carbon (50 mg) under 3 bar of hydrogen. The reaction mixture was filtered and the solvent was removed in vacuo to yield the title compound (78 mg, 75%) as a yellow solid. MS ISP (m/e): 193.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.93 (s, 1H), 7.16 (dd, 1H), 6.51 (m, 2H), 4.03 (s broad, 2H), 2.38 (s, 3H). Mp 106-108° C.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[F:8][C:9]([F:27])([F:26])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[N:14][CH:15]=1.CN(CN(C)C)C>>[F:27][C:9]([F:8])([F:26])[C:10]1[CH:11]=[CH:12][C:13]([C:16](=[CH2:1])[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[N:14][CH:15]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)CN(C)C
Product: C=C(C(=O)c1ccc(Cl)cc1)c1ccc(C(F)(F)F)cn1

Procedure:
Acetic anhydride (19 mL, 21 g, 200 mmol) was added slowly to a stirring slurry of 2-(5-trifluoromethyl-2-pyridinyl)-1-(4-chlorophenyl)ethanone (12.1 g, 40.0 mmol) in bisdimethylaminomethane (22 mL, 16 g, 160 mmol) at 0° C. causing immediate solution. TLC showed complete conversion after 5 min and the mixture was partitioned between ether and water by adding these solvents and separating the layers. The organic layer was extracted with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain 13 g (99 percent of theory) of the title compound as a red oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[O:30]1[C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=[N:31]1>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:35]([C:34]3[O:30][N:31]=[CH:32][CH:33]=3)=[O:36])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccno4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (2.7 g, 8.4 mmol) in CH3CN (25 ml), were added triethyl amine (2.9 mL, 8.4 mmol) and isoxazole-5-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL). The solid was dissolved in CH2Cl2 (5 mL) and purified by ISCO silica gel flash chromatography (eluent: 2% MeOH in CH2Cl2) to afford isoxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a light yellow solid (0.87 g, 27%): mp, 257-259° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.62 (99%); 1H NMR (DMSO-d6): δ 2.04-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.93 (d, J=5.6 Hz, 2H), 5.17 (dd, J=6, 12 Hz, 1H), 7.14-8.78 (m, 5H), 9.60 (t, J=5.6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 37.96, 48.87, 106.26, 122.11, 127.25, 131.56, 133.14, 134.89, 138.00, 151.75, 155.95, 162.35, 166.90, 167.44, 169.80, 172.73. Anal Calcd for C18H14N4O6: C, 56.55; H, 3.69; N, 14.65. Found: C, 56.20; H, 3.36; N, 14.47.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[SH:7].Br[CH2:9][CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCBr
Reactant: Cn1cnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cnnc1SCCCO
Temperature: 40 °C
Yield: 29.4 %

Procedure:
A solution of 4-methyl-4-H-1,2,4-triazole-3-thiol (1.72 g, 15 mmol) and 3-bromopropan-1-ol (1.39 g, 10 mmol) in DMF (10 ml) containing potassium carbonate (1.57 g, 14 mmol) was heated at 40° C. for 30 minutes. The mixture was then partitioned between saturated ammonium chloride and ethyl acetate. The aqueous layer was evaporated to dryness and the residue was triturated with ethyl acetate and methylene chloride. The suspension was filtered and the filtrate was dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol (510 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][C:5]([C:10]([CH3:12])=[CH2:11])=[C:4]([CH3:13])[N:3]=1.[BH4-].[Na+].Cl>CCO>[CH:10]([C:5]1[CH:6]=[C:7]([CH2:8][NH2:9])[C:2]([CH3:1])=[N:3][C:4]=1[CH3:13])([CH3:12])[CH3:11]
Reactant: C=C(C)c1cc(CN)c(C)nc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(C)c(C(C)C)cc1CN
Reaction time: 2 h

Procedure:
To a solution of crude (2,6-dimethyl-5-(prop-1-en-2-yl)pyridin-3-yl)methanamine and 120 mg (0.505 mmol) of CoCl2.6H2O in 5 mL of EtOH at 50° C. was added 115 mg of NaBH4 in 2 portions. After 2 h, 5N HCl was added to a pH=1 and stirring was continued until the bubbling ceased. The mixture was concentrated, and NH4OH was added to pH=9. Some water was added, and the aqueous layer was extracted with the extract of (40 mL CHCl3: 5 mL MeOH: 5 mL H2O). The combined extracts were dried over Na2SO4, filtered, and concentrated to give the crude (5-isopropyl-2,6-dimethylpyridin-3-yl)methanamine which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[N+:20]([C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29][NH:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([N:30]2[C:31]3[C:26](=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:32]=3)[CH2:27][CH2:28][CH2:29]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 5-chloro-2-methoxybenzenesulfonyl chloride (2.75 g, 11.20 mmol) in dichloromethane (0.15 L) was treated with pyridine (14.59 mL, 181.26 mmol) and a solution of 7-nitro-1,2,3,4-tetrahydro-quinoline (1.90 g, 10.66 mmol) in dichloromethane (6.00 mL). The mixture was stirred at room temperature for 120 hours, then the volatiles were evaporated. The residue was redissolved in dichloromethane and washed with water. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (dichloromethane/methanol gradient) to yield 1-(5-chloro-2-methoxy-benzenesulfonyl)-7-nitro-1,2,3,4-tetrahydro-quinoline as an orange solid, 3.46 g (85%), MS (ISP): m/e=383.1 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:21])[C:5](=O)[CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]2[S:14][C:15]([F:17])=[CH:16][C:12]=2[CH:11]=1.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:17][C:15]1[S:14][C:13]2[CH:18]=[CH:19][C:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][N:4]([CH3:21])[CH2:3][CH2:2][OH:1])=[CH:11][C:12]=2[CH:16]=1
Reactant: CN(CCO)C(=O)COCCc1ccc2sc(F)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(CCO)CCOCCc1ccc2sc(F)cc2c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
In 7 mL of tetrahydrofuran is dissolved 0.70 g of N1-(2-hydroxyethyl)-N1-methyl-2-[2-(2-fluorobenzo[b]thiophen-5-yl)ethoxy]-acetamide. The solution is cooled to 5° C., to which is dropwise added 6.7 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran. The resulting mixture is stirred at ambient temperature overnight, 1.5 mL of 6 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for one hour. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 10.5 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1 to 5:1) to obtain 0.58 g of 2-[{2-[2-(2-fluorobenzo[b]thiophen-5-yl)ethoxy]ethyl}(methyl)amino]-1-ethanol as an oily product.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22]CO)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:2][CH:1]=[O:5])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NC(CCO)c1ccccc1)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCC(NC(=O)OCc1ccccc1)c1ccccc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
To a stirred solution of oxalyl chloride (1.6 mL, 18.2 mmol) in methylene chloride (20 mL) at −50° C. was added drop-wise a solution of DMSO (2.84 g, 36.4 mmol). The resulting mixture was stirred at −50° C. for 15 minutes, and a solution of (3-hydroxy-1-phenyl-propyl)-carbamic acid benzyl ester (4.7 g, 16.53 mmol) in methylene chloride 35 mL). The mixture was stirred at −50° C. for 15 minutes, then TEA (11.5 mL, 82.7 mmol) was added. The mixture was stirred for five minutes at −50° C., then allowed to stir at room temperature for 30 minutes. The reaction mixture was washed with 5% aqueous HCl, dried over MgSO4, filtered and concentrated under reduced pressure to give 4.7 g (100%) of (4-oxo-1-phenyl-butyl)-carbamic acid benzyl ester as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].CN(C)C=O.Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:1][CH:2]=1
Reactant: CC(C)=CCBr
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCOc1ccc(C)cc1

Procedure:
A mixture of p-cresol and sodium hydroxide was stirred with dimethylformamide and water while 1-bromo-3-methylbut-2-ene (VII; R1 =R2 =CH3, Hal=Br) was added dropwise. The 1-(p-methylphenoxy-3-methylbut-2-ene was isolated as described under Example B(i).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:13]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:15])[CH3:14]
Reactant: CC(C)Br
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC(C)C)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Methyl 3-hydroxybenzoate (1 eq.) and 2-bromopropane (2 eq.) were dissolved in DMF. Subsequent to addition of potassium carbonate (2 eq.), the resulting mixture was stirred at 100° C. for 24 hours. The mixture was charged into water. Subsequent to extraction with ethyl acetate, the organic layer was washed with 1 N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, whereby the title compound was obtained (yield: 49%).
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.CCOCC>C(O)C.CO>[ClH:23].[ClH:23].[C:1]1([C:7](=[N:22][NH:21][C:18]([NH2:20])=[NH:19])[C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: N=C(N)NN=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 154.7 %

Procedure:
To a solution of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (0.15 g, 0.67 mmol) in ethanol (6.7 mL) were added aminoguanidine hydrochloride (0.09 g, 0.81 mmol) and 6 N HCl (0.56 mL). The reaction mixture was heated to reflux under N2. After 3 h, heating was terminated and the reaction mixture was slowly cooled to room temperature overnight. The reaction mixture was concentrated to dryness. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was made basic with 15% NaOH solution and extracted with ethyl acetate (2×). The organic extracts were combined and washed with water and saturated NaCl, and dried over Na2SO4. Filtration and concentration provided the crude residue, which was dissolved in methanol. To the methanol solution was added 2 N HCl in Et2O (0.67 mL, 1.34 mmol). The mixture was concentrated to dryness and the resulting solid was crystallized from EtOH/Et2O (9:1) to provide [[phenyl (1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]guanidine dihydrochloride (0.22 g, 93%) as an off-white solid: mp 306-310° C.; 1H NMR (300 MHz, CD3OD) δ6.71 (1H, s), 7.57-7.74 (5H, m), 8.07 (1H, d, J=6.5 Hz), 8.24 (1H, d, J=6.4 Hz), 9.10 (1H, s); ESI MS m/z 279 [C15H14N6+H]+; HPLC (Method A) >99% (AUC) tR=12.9 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]=2[CH3:23])=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[C:28]([O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]([CH3:23])=[C:10]2[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:30])[CH3:29])[CH3:25]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(CCc2ccc(Cl)cc2)c2cc(O)ccc21
Product: CCCn1c(C)c(CCc2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-[2-(4-chloro-phenyl)-ethyl]-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.