Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[CH2:16][CH2:17][C:18](=[CH:20][C:21]#[N:22])[C:19]=3[C:11]=2[N:10]=[C:9]1[CH3:23])C1C=CC=CC=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N.C(O)C.[Co]>[CH3:23][C:9]1[NH:10][C:11]2[C:19]3[CH:18]([CH2:20][CH2:21][NH:22][C:31](=[O:33])[CH3:32])[CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][C:12]=2[N:8]=1
Reactant: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=CC#N
Reactant: CC(=O)OC(C)=O
Agent: [Co]
Agent: N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1CCc2ccc3nc(C)[nH]c3c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
(3-Benzyl-2-methyl-6,7-dihydroindeno[4,5-d]imidazol-8(3H)-ylidene)acetonitrile was dissolved in 2M ammonia/ethanol solution (14 mL), Raney cobalt (10 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL), triethylamine (34.9 μL, 0.25 mmol) and acetic anhydride (18.9 μL, 0.20 mmol) were added, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→15/85). The purified product was dissolved in methanol (3 mL), palladium-carbon powder (20 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→20/80) to give the title compound (13.4 mg, yield 31%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH:18]([CH3:20])[CH3:19])=[C:10]([CH2:12][C:13]([O:15]CC)=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[K+]>O>[C:1]1([C:7]2[O:8][C:9]([CH:18]([CH3:20])[CH3:19])=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)oc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1oc(-c2ccccc2)nc1CC(=O)O
Yield: 97.6 %

Procedure:
2.73 g of ethyl 2-(2-phenyl-5-isopropyl-4-oxazolyl)acetate, 20 ml of methanol, 5 ml of water and 1.1 g of potassium hydroxide are treated in the same manner as described in Example 8. 2.39 g of 2-(2-phenyl-5-isopropyl-4-oxazolyl)acetic acid are thereby obtained. Yield: 97.4%.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32]Cl)[CH3:29].[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>>[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2)[CH3:29]
Reactant: CCN(CC)CCCl
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cl
Agent: [H-]
Product: CCN(CC)CCON=C1CC(c2ccccc2-c2ccccc2)Cc2nc(N)nc(C)c21

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (30 mg, 0.087 mmol), 2-diethylaminoethylchloride hydrochloride (30 mg, 0.221 mmol) and sodium hydride (60% dispersion in oil) (18 mg, 0.470 mmol) following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88).
Reaction SMILES: C(P(O)(=O)O)(P(O)(=O)O)C(P(O)(=O)O)CCCCCCCCCC.OC(P(O)(=O)O)(P(O)(=O)O)CCCCCCCCCCC.[C:46]([OH:59])(=[O:58])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]CCC>C(P(=O)(OCCCC)OCCCC)CCC.P(=O)(O)(O)O>[C:46]([OH:59])(=[O:58])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCC(C(P(=O)(O)O)P(=O)(O)O)P(=O)(O)O
Agent: CCCCCCCCCCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: CCCCOP(=O)(CCCC)OCCCC
Product: CCCCCCCCC(=O)O

Procedure:
In similar manner C9, C12, C16 and C18 extractants were prepared at 150° C. from iso-nonanoic, lauric, iso-hexadecanoic and stearic acids respectively. NMR analysis of the C12 extractant revealed that dodecane-1,1,2-triphosphonic acid was a major component of the crude product and that 1-hydroxy-1,1-dodecane diphosphonic acid was absent. When a solution of the crude C12 extractant (10 wt %) in dibutyl butylphosphonate (10 wt %) and kerosene (80 wt %) was shaken with equal volume of 10 M phosphoric acid, the total carbon in the phosphoric acid was 0.01%. The same amount of carbon was found when a 10 wt % kerosene solution of dibutyl butyl phosphonate was used instead. These results indicate that loss of material from the crude C12 extractant during contact with phosphoric acid is negligible. A C12 extractant was also made from lauric acid by reaction at 110° C. for 16 h. The main component of this acid extractant was 1-hydroxy-1,1 -dodecanediphosphonic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-])=O)[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]([NH2:18])[C:14]([NH:30][CH2:29][CH2:28][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(F)c([N+](=O)[O-])c3)nc12
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(NCCN4CCOCC4)c(N)c3)nc12
Temperature: 180 °C

Procedure:
5-Chloro-4-methylpyridine-2,3-diamine (Example 249b) (1.47 g, 9 mmol) and 4-fluoro-3-nitrobenzoic acid (1.73 g, 9 mmol) were mixed in phosphorous oxychloride (50 ml) and heated to 110° C. for 64 h. When cool, the excess phosphorous oxychloride was removed in vacuo to afford a brown semi-solid (about 4 g) consisting of 6-chloro-2-(4-fluoro-3-nitrophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine and various inorganic material. To 1.0 g of this crude material, (2-morpholin-4-ylethyl)amine (2 ml) was added and the mixture heated in the microwave oven (180° C., 20 min).
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([O:16][CH2:17][CH2:18][C@H:19]([OH:41])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(O[CH2:47][CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=O)=O>CS(C)=O.O>[CH2:9]([O:16][CH2:17][CH2:18][C@H:19]([O:41][CH2:47][CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:20][O:21][C:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O[C@@H](CCOCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCCC
Product: c1ccc(COCCO[C@@H](CCOCc2ccccc2)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Sodium hydride (6.32 g, 0.158 mmol, 60% in oil) was loaded under argon circumstance in three-necked flask and hexane (100 ml) was added thereto. After stirring for a while, it was allowed to stand and the supernatant was removed by syringe. By repeating this procedure three times, the oil of sodium hydride was removed. After drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (30 ml) was added and the solution was stirred at 60° C. for 1 hour. After cooling to room temperature, (S)-4-benzyloxy-1-trityloxy-2-butanol (55.89 g, 0.132 mol) in DMSO (40 ml) was gradually dropped at room temperature to the solution and then the solution was stirred for 30 minutes. To the solution was gradually dropped 2-benzyloxyethyl methanesulfonate (33.4 g, 0.145 mol) in DMSO (40 ml) at room temperature and then the solution was stirred for 12 hours. To the reaction mixture was added water (120 ml) and the solution was extracted with ethyl acetate. The extract was washed with water (150 ml) twice and with saturated brine once, dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-benzyloxy-2-(2-benzyloxyethoxy)-1-trityloxybutane (55.0 g, yield 75%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.CC(C)([O-])C.[K+].[CH2:21]([CH2:28][C:29](=O)[CH3:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[C:22]1([CH2:21][CH2:28][C:29]([CH3:30])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 123.5 %

Procedure:
Ethyl diethylphosphonoacetate (1.67 g, 7.42 mmol) was added dropwise to a solution of potassium tert-butoxide (0.83 g, 7.42 mmol) in tetrahydrofuran (10 ml), followed by stirring at room temperature for 10 minutes. Then, a solution of benzylacetone (1.00 g, 6.75 mmol) in tetrahydrofuran (10 ml) was added drop-wise thereto, and the resulting mixture was stirred at room temperature for 1 hour and then heated under reflux for another 1 hour. The reaction mixture was poured into a 5% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate. The extract solution was washed with water and an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.82 g of ethyl 5-phenyl-3-methyl-2-pentenoate.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][CH:11]=[C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:21]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.Cl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:21][C:20]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=3)[CH:11]=[C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1
Reactant: CC(C)Cc1nn(C)c(=O)c2c[nH]cc12
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Cn2cc3c(CC(C)C)nn(C)c(=O)c3c2)cc(OC)c1OC
Reaction time: 16 h

Procedure:
A mixture of 2,6-dihydro-2-methyl-4(2-methylpropyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (Example 18 step a, 0.031 g), 3,4,5-trimethoxybenzyl chloride (0.038 g), and cesium carbonate (0.090 g) in dry dimethyl formamide (0.8 ml) was stirred for 16 hours, and then diluted with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, which was washed with brine, dried, and evaporated to a solid. The solid was purified by chromatography on silica (dichloromethane/ethanol 9:1) to give 2,6-dihydro-2-methyl-4-(2-methylpropyl)-6-[3,4,5-trimethoxyphenyl]methyl-1H-pyrrolo[3,4-d]pyridazin-1-one (0.033 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[C:4]([N+:14]([O-])=O)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>C(O)(=O)C.[Fe]>[NH2:14][C:4]1[C:5]([O:12][CH3:13])=[C:6]([CH:11]=[C:2]([Br:1])[C:3]=1[F:17])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(F)c([N+](=O)[O-])c1OC
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(F)c(N)c1OC
Temperature: 130 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
Methyl 5-bromo-4-fluoro-2-methoxy-3-nitrobenzoate (I-229) (1.0 g, 3.25 mmol) was dissolved in acetic acid (10 ml), and at room temperature, iron powder (544 mg, 9.74 mmol) was added, followed by stirring at 130° C. for 4 hours. After cooling to room temperature, the insoluble matter was separated by filtration with washing with ethyl acetate. The organic layer of the filtrate was evaporated under reduced pressure, and the resulting residue was fractionated with ethyl acetate and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=4:1) to obtain the entitled compound (798 mg, 88%) as a colorless gel substance.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.[ClH:32]>C(O)C>[ClH:32].[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:6]2[O:5][C:4]([NH:7][CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]2=[O:1])=[CH:22]1
Reactant: CCOC(=O)C1=C(NCCc2ccccc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(NCCc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 32 %

Procedure:
To a solution of ethyl 4-oxo-2-(phenethylamino)-4,5-dihydrofuran-3-carboxylate (0.041 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.023 g, y. 32%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[OH-].[NH4+:13]>O1CCOCC1>[Br:1][C:2]1[C:6]2[C:7]([NH2:13])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: Clc1nccc2occ(Br)c12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc2occ(Br)c12
Temperature: 150 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
A mixture of 3-bromo-4-chlorofuro[3,2-c]pyridine (7.0 g, 22 mmol), 38 wt % aqueous ammonium hydroxide (75 mL) and dioxane (75 mL) in a Parr mini-reactor was stirred at 150° C. for two days. The solvent was removed in vacuo and water (200 mL) was added to the residue. The mixture was adjusted to pH 12 with 2N NaOH (aq) extracted with ethyl acetate (5×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (4.6 g, 71%). 1H NMR (DMSO-d6, 400 MHz) 8.13 (s, 1H), 7.85 (d, 1H), 6.92 (d, 1H), 6.17-6.27 (bs, 2H); RP-HPLC (Conditions d) Rt 8.02 min.; MS: MH+ 213, 215.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([CH:23]([CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=[O:25])[CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O1CCCC1>[CH2:13]([CH:23]([CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]([OH:25])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC/C=C\CCCC(C=O)CCC/C=C\CCCCC
Reactant: CCCCC/C=C\CCCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of magnesium turnings (0.6 g, 23.9 mmol) in tetrahydrofuran (5 mL) was slowly added a solution of (Z)-1-bromodec-4-ene 3 (4.5 g, 20.5 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 30 minutes at room temperature then a solution of (Z)-2-((Z)-dec-4-enyl)dodec-6-enal 7 in tetrahydrofuran (5 mL) was added. The solution was stirred for 15 minutes at room temperature then poured into 5% hydrochloric acid (50 mL) and ice (100 mL). The solution was extracted with ether (2×150 mL). The combine ether extracts were dried on magnesium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography (1% ethyl acetate in hexanes) to afford (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 as a colorless oil (4.8 g, 76%). Rf 0.45 (10% EtOAc-Hexanes).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:7][CH2:8]C(O)=O)=[CH:5][CH:6]=1.C([Li])CCC.[N+:17]([O-])([O:19]CCC(C)C)=[O:18]>CCCCCC>[CH3:1][C:2]1[S:3][C:4]([S:7][CH2:8][N+:17]([O-:19])=[O:18])=[CH:5][CH:6]=1
Reactant: CC(C)CCO[N+](=O)[O-]
Reactant: Cc1ccc(SCC(=O)O)s1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1ccc(SC[N+](=O)[O-])s1
Yield: 9 %

Procedure:
The starting material was obtained using a similar procedure to that described for that in Example 9, but starting with 2-(2-methylthien-5-ylthio)acetic acid (described in Zh. Obsch. Khim. 1959, 29, 3631; 8.87 g), adding the butyllithium in hexane at -30° C. and the isoamyl nitrate at 0° C. The product 2-methyl-5-(nitromethylthio)thiophene, was obtained as an oil in 9% yield after column chromatography eluting with 10% ethyl acetate/hexane; NMR: 2.48 (s,3H), 5.38 (s,2H), 6.7 (m,1H), 7.1 (d,1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(C=O)c(F)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (653, 1.62 g, 9.52 mmol) was dissolved in N,N-dimethylformamide (50 mL) and sodium hydride (60% dispersion in mineral oil, 530 mg, 13 mmol) was added. After 20 minutes, benzyl bromide (1.5 mL, 12 mmol) was added to the reaction mixture. The reaction was stirred at room temperature under an atmosphere of nitrogen for 5.5 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 0-50% ethyl acetate in hexane to provide compound as a white solid, consistent with the desired structure by 1H-NMR (654, 2.0 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][N:5]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:6][CH3:7].[Br:20]Br>C(Cl)Cl>[NH2:1][C:2]1[C:17]([Br:20])=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][N:5]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:6][CH3:7]
Reactant: BrBr
Reactant: CCN(Cc1cc(OC)ccc1N)C1CCCCC1
Solvent: ClCCl
Product: CCN(Cc1cc(OC)cc(Br)c1N)C1CCCCC1

Procedure:
2-Amino-3-bromo-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine was prepared from 2-amino-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([N:18]=[C:19]2[NH:23][CH2:22][CH2:21][NH:20]2)=[C:13]([Cl:24])[CH:12]=1)(OC)=[O:8].C(OCC)(=O)C>O1CCCC1>[Cl:24][C:13]1[CH:12]=[C:11]([CH2:7][OH:8])[CH:16]=[C:15]([Cl:17])[C:14]=1[N:18]=[C:19]1[NH:20][CH2:21][CH2:22][NH:23]1
Reactant: COC(=O)c1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Yield: 48.7 %

Procedure:
Lithium aluminium hydride (300 mg, 7.9 mM) was added to a stirred suspension of 2-(4-carbomethoxy-2,6-dichlorophenylimino)imidazolidine (750 mg, 2.6 mM) in dry tetrahydrofuran (50 ml) with stirring. The mixture was then stirred at room temperature for several hours after which time ethyl acetate was carefully added. The solvent was then removed under vacuum and water was added to the residue. After basification with dilute sodium hydroxide the aqueous mixture was extracted several times with ethyl acetate. The extract (750 mg) was dried and evaporated to give a solid which was recrystallised from isopropanol to give a white solid (330 mg) mp 208°-210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[BH3-]C#N.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Cc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc2c1CCN2
Yield: 92.2 %

Procedure:
To a solution of 4-methylindole (7.433 g, 0.0567 mol) in 100 mL of glacial acetic acid was added NaCNBH3 (7.25 g, 0.12 mol) portionwise over 1.5 h. The reaction mixture was then concentrated in vacuo water was added and the solution was basified with 10N NaOH. The resulting mixture was extracted with ethyl acetate (×3) and the organic extract was washed (brine), dried (Na2SO4) and evaporated to give an oil. Flash chromatography (SiO2 /ethyl acetate-hexane, 1:4) of this oil gave pure 4-methylindoline (6.962 g, 92%) as an oil: 1H NMR (DMSO-d6, 200 MHz) δ6.78 (t, J=7.6 Hz, 1H), 6.33 (d, J=7.4 Hz, 1H), 6.30 (d, J=7.6 Hz, 1H), 5.36 (br s, 1H), 3.38 (t, J=8.5 Hz, 2H), 2.81 (t, J=8.5 Hz, 2H), 2.11 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[C:11](I)[C:10]=2[CH:9]=1)#[N:2].[CH2:36]1COCC1.[Cl-].C[Zn+]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[C:11]([CH3:36])[C:10]=2[CH:9]=1)#[N:2]
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Reactant: C1CCOC1
Agent: C[Zn+]
Agent: [Cl-]
Product: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C#N)c4)cc13)CCC2CC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
tert-Butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.717 g, 1.223 mmol) was dissolved in anhydrous THF (12.2 mL, 1.223 mmol). The solution was degassed with nitrogen for about 5 min using a syringe needle. Bis(tri-t-butylphosphine)Pd(0) (0.056 g, 0.110 mmol) and 2.0 M methylzinc chloride in THF (1.83 mL, 3.67 mmol) were added. The reaction vessel was purged with nitrogen, sealed, and heated at 70° C. After 2 h, the reaction mixture was cooled to 25° C. and slowly added saturated NaHCO3 (5 mL). After stirring for about 5 min, the reaction was diluted with EtOAc (20 mL), filtered through a celite pad, and the celite pad was washed with EtOAc (3×20 mL). The organic layer was washed with water (2×20 mL), brine (10 mL), and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to give the title compound as an oil (0.470 g). LCMS m/z=475.4 [M+H]+; 1H NMR (400 MHz, Acetonitrile-d3) δ ppm 1.36 (d, J=5.94 Hz, 6H), 1.41 (s, 9H), 2.19 (s, 3H), 2.27-2.37 (m, 1H), 2.46 (dd, J=15.66, 9.22 Hz, 1H), 2.72-2.86 (m, 2H), 3.60-3.69 (m, 1H), 3.93 (m, 1H), 4.00-4.10 (m, 1H), 4.75 (dt, J=12.13, 6.06 Hz, 1H), 5.03 (s, 2H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.00 (d, J=2.40 Hz, 1H), 7.11 (d, J=8.72 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.63-7.68 (m, 1H), 7.69 (d, J=2.27 Hz, 1H).