Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CC[C@@H](COC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 143–146° C.; 1H NMR (300 MHz, CDCl3): δ 7.16 (d, J=1.9 Hz, 1 H), 7.09 (d, J=1.9 Hz, 1 H), 7.03 (s, 1 H), 4.93–4.88 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.65 (dd, J=10.6, 5.5 Hz, 1 H), 3.54 (dd, J=10.6, 3.5 Hz, 1 H), 3.33 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.90–1.70 (m, 2 H), 0.91 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2Cl3 (M+H)+: 402.0543; found m/z 402.0520.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:27]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NCCOc1cccc2c1CC(N(CCC)CCC)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene were initially introduced into 25 ml of toluene. The reaction was catalyzed using 3 drops of thiethylamine, and 0.63 ml (5.5 mmol) of butyl isocyanate was then added dropwise. The mixture was stirred for 2 h at room temperature. The mixture was evaporated to dryness, and the residue was crystallized from petroleum ether/diisopropyl ether.
Reaction SMILES: [CH:1]1([C@@H:4]2[C:11]3[C:7](=[N:8][NH:9][CH:10]=3)[CH:6]([CH2:12][OH:13])[NH:5]2)[CH2:3][CH2:2]1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1.C(Cl)Cl>[CH:1]1([C@@H:4]2[C:11]3[C:7](=[N:8][NH:9][CH:10]=3)[CH:6]([CH2:12][OH:13])[N:5]2[S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:26])[F:27])=[CH:21][CH:20]=2)(=[O:24])=[O:23])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: OCC1N[C@H](C2CC2)c2c[nH]nc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1C(CO)c2n[nH]cc2[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
((4R)-4-cyclopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-yl)methanol (36) (627 mg, 3.50 mmol) and 4-trifluoromethylbenzenesulfonyl chloride (2.57 g, 10.5 mmol) were dissolved in pyridine (5 mL) and the resulting mixture was stirred at rt for 12 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with 1 N aq. HCl (10 mL). The aq. phase was separated and extracted once with CH2Cl2 (10 mL) and the combined organic phases were then dried (Na2SO4), filtered and concentrated under vacuum. The residue was dissolved in THF (5 mL) and 3 N aq. NaOH (3.5 mL) was added. The resulting mixture was stirred at rt for 18 h and was subsequently extracted with EtOAc. The organic phase was then dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give ((4R)-4-cyclopropyl-5-(4-(trifluoromethyl)phenylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-yl)methanol (37) as a white solid. Retention time (min)=5.573, method [7], MS (m/z) 410.0 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.CO[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][Si](C)(C)C.C([O:26][C:27](=[O:38])[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)C.[OH-].[Na+]>C(Cl)Cl>[CH2:17]([N:11]1[CH2:10][C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)=[C:28]([C:27]([OH:38])=[O:26])[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C#Cc1ccc(F)c(F)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(c2ccc(F)c(F)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At r.t., trifluoroacetic acid (0.11 ml, 1.34 mmol, 0.1 eq.) followed by N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (4.89 g, 20.2 mmol, 1.5 eq.) were added dropwise to a stirred solution of (3,4-difluoro-phenyl)-propynoic acid ethyl ester (2.83 g, 13.5 mmol) in CH2Cl2 (80 ml). The yellow solution was stirred at r.t. for 18 h. Trifluoroacetic acid (0.034 ml, 0.44 mmol, 0.033 eq.) and N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl) methylamine (1.66 g, 6.73 mmol, 0.5 eq.) were added, and the solution was stirred for 1 h. It was evaporated to dryness, and the residue was dissolved in dioxane (40 ml). An aqueous solution of NaOH (18.7 ml, 37.4 mmol, 2.8 eq.) was added. The resulting emulsion was stirred at r.t. for 18 h, and the low boiling organic solvent was removed under reduced pressure. Water (40 ml) was added, and the aqueous layer separated and washed twice with TBME (50 ml). The organic layers were washed with the same portion of water (15 ml). The combined aqueous layers were acidified by addition of aqueous 3M HCl (12.4 ml). The resulting suspension was stirred for 48 h at r.t. The white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 4.25 g (58%) of IIc as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])S(C)(=O)=O)(=[O:4])=[O:3].O.[OH-].[Li+].Cl>CO>[CH3:1][S:2]([NH:5][C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate (22.9 g) and lithium hydroxide monohydrate (7.5 g) in aqueous methanol (50%) was stirred at room temperature for 18 hours. The resulting solution was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige solid, NMR (acetone d6); 3.1(2s,6H), 7.57(dd,1H), 8.15(d,1H), 8.23(d,1H).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:35])([CH3:34])[CH2:7][C@H:8]([N:25]([C:27](OC(C)(C)C)=[O:28])[CH3:26])[CH2:9][O:10][C:11](=[O:24])[NH:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=2)(=O)C.Cl.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[C:66]([F:67])=[CH:65][CH:64]=[CH:63][C:48]=1[CH2:49][NH:50]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[F:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[N:14][C:13]([NH:12][C:11](=[O:24])[O:10][CH2:9][C@@H:8]([N:25]([CH3:26])[C:27]([NH:50][CH2:49][C:48]1[CH:63]=[CH:64][CH:65]=[C:66]([F:67])[C:47]=1[Cl:46])=[O:28])[CH2:7][C:6]([CH3:35])([CH3:34])[CH2:5][OH:4])=[CH:22]2
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCC(C)(C)C[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(C)(C)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)-2,2-dimethylpentyl acetate (1.9 g, 3.8 mmol) in THF (50 mL) was added HCl (4 N in 1,4-dioxane, 19 mL, 76 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness. The residue was suspended in THF (100 mL). To the suspension were added DIEA (2.0 mL, 11.4 mmol) and 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (1.2 g, 3.8 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-hydroxy-4,4-dimethylpentyl 6-fluoroisoquinolin-3-ylcarbamate (1.1 g, 53%). LRMS (M+H+) m/z 535.5
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:14]=[C:13](Cl)[C:12]([CH3:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:7]([C:13]1[C:12]([CH3:16])=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[C:9]([CH3:8])[CH:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccccc1

Procedure:
A solution of 4.44 g (47 mmol) of phenol and 8.76 g (47 mmol) of 2,5-dimethyl-4-chloro-nitrobenzene in 50 ml of DMF was admixed with 9.78 g (71 mmol) of K2CO3 and the mixture was heated under reflux for 10 h.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH3:16].C(N(C(C)C)CC)(C)C>CCO>[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH3:16])[C:7]1[CH:6]=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CNCCOC
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1ccc([N+](=O)[O-])nc1
Temperature: 90 °C
Yield: 41 %

Procedure:
A solution of 2-nitro-5-bromopyridine (500 mg, 3.15 mmol) in EtOH (15 mL) was treated with methoxyethyl-N-methylamine (1.12 g, 12.6 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol). The resulting mixture was then heated in a sealed tube at 90° C. for 4 days then cooled and partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes gradient to afford the product as a thick yellow oil that crystallized slowly upon standing (270 mg, 41% yield). HRMS m/z calcd for C9H13N3O3 [M+Na]+: 234.0849; Found: 234.0850.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].C[O-].[Na+].[CH:9]12[O:14][CH:10]1[CH2:11][CH2:12][CH2:13]2>CO>[OH:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: C1CC2OC2C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CS[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Mercaptoacetic acid (22.5 g 0.244 mole) was added to a cold (+5° C.) solution of sodium methoxide [prepared from sodium (11.2 g, 0.488 mole)] in methanol (125 ml). After stirring for 20 minutes, cyclopentene oxide (19.5 g, 0.23 mole) was added dropwise over 20 minutes to the cold solution. The ice bath was removed and the reaction was refluxed for 45 minutes. The reaction was cooled to room temperature and made acidic by the addition of 4 N hydrochloric acid. Water (100 ml) was added and the mixture was extracted twice with 150 ml of diethyl ether. The combined diethyl ether extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:24][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:24]([CH3:25])[C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2ccccc2OC)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution of 0.30 g (0.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.19 g (1.31 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt with ethanolic HCl to yield 0.41 g (89%) of the title compound as a white solid; mp=222-224° C.; MS (+) ESI m/z=456 (M+H)+.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1)C.[NH2:30][NH:31][C:32](=O)[CH2:33][N:34]([CH3:36])[CH3:35].C[O-].[Na+]>CO>[CH3:35][N:34]([CH2:33][C:32]1[NH:31][N:30]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:36]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)CC(C)(C)C)c3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)CC(C)(C)C)c4)c3c2)n[nH]1

Procedure:
The title compound was prepared according to the procedure described in Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3,3-dimethylbutanamide hydrochloride (0.360 g, 0.87 mmol), N-amino-2-(dimethylamino)acetamide (0.304 g, 2.60 mmol) and sodium methoxide in methanol (0.398 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.093 g, 25% yield): 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.16 (t, 1H), 8.08 (dt, 1H), 7.75 (dt, 2H), 7.66 (d, 1H), 7.50 (t, 1H), 3.71 (s, 2H), 2.37 (s, 6H), 2.30 (s, 2H), 1.12 (s, 9H),
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:3][CH:2]=1.O>C(OCC)C>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH:7]([OH:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:5][CH:6]=1
Reactant: C=CCCCC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: C=CCCCC(O)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
1-Biphenyl-4-yl-hex-5-en-1-one (1 g) was dissolved in diethyl ether (25 ml) NaBH4 (2.5 g) was added and the mixture stirred for 30 minutes. Water (50 ml) was added and most of the solvent evaporated under vacuo. The residue was poured into water and the product extracted with ethyl acetate. The orgahic layer was dried (Na2SO4) and the ethyl acetate evaporated under vacuum to give a white solid. δC (CDCl3, 62.9 MHz): 25.2, 33.6, 38.5, 74.3, 114.8, 126.4, 127.1, 127.2, 128.8, 138.6, 140.5, 140.9 and 143.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([C:16]([O:18]C)=[O:17])=[N:14][CH:13]=[CH:12][N:11]3[CH:20]=2)=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([C:16]([OH:18])=[O:17])=[N:14][CH:13]=[CH:12][N:11]3[CH:20]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 50 °C
Yield: 156 %

Procedure:
The crude methyl 2-(4-fluorophenyl)imidazo[1,2-a]pyrazine-8-carboxylate (35.7 g, 65.8 mmol) was dissolved in 1,4-dioxane (200 mL), then water (20.2 mL) and lithium hydroxide monohydrate (27.6 g, 658 mmol) were added. Heated to about 50° C. overnight. The reaction mixture was cooled to ambient temperature, filtered, and the collected solid was washed with Et2O (4×70 mL). The resulting brown solid was suspended in water (200 mL) and the pH was adjusted to ˜5 with glacial HOAc (100 mL). The solid was collected, washed with water (4×75 mL) and Et2O (2×80 mL) to give the wet crude title compound (26.4 g, 156%) that was carried on without further purification. LC/MS (Table 1, Method b) Rt=1.21 min; MS m/z: 258.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[N:22]=[CH:23][N:24]([CH3:26])[CH3:25])[NH:5]C(OCC1C=CC=CC=1)=O.O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[N:22]=[CH:23][N:24]([CH3:26])[CH3:25])[NH2:5]
Reactant: COC(=O)[C@H](Cn1ccnc1N=CN(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](N)Cn1ccnc1N=CN(C)C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
3- (2-Dimethylaminomethyleneaminoimidazol-1-yl)-N-(benzyloxycarbonyl)-L-alanine methyl ester (937 mg) was dissolved in methanol (25 ml), and 50% water-containing 10% Pd/C (468 mg) was added. Then, the mixture was vigorously stirred for 2 hours under an atmosphere of hydrogen. The catalyst was filtered off. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (eluent: 7% ammonia-containing ethanol-chloroform a 3:97) to give the title compound (482 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[OH-].[K+].CCOCC>[Cu]I.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:6]=[C:5]2[CH3:11]
Reactant: Cc1c[nH]c2ccc(Br)cc12
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cn(-c2ccc(F)cc2)c2ccc(Br)cc12
Yield: 12.3 %

Procedure:
To 4.2 g (20 mmol) 5-Bromo-3-methyl-1H-indole [prepared according to Noland, Wayland E.; Reich, Charles. Synthesis and reactions of 5-bromoskatole and 5-bromo-1,3-dimethylindole. J. Org. Chem. (1967), 32(3), 828-32.] in 22 ml (0.2 mol) 1-bromo-4-fluorobenzene were added 5.6 g (0.1 mol) powdered potassium hydroxide and 1.14 g (60 mmol) CuI as powder. The suspension was heated to reflux for 0.5 h. At RT, ether and water were added, the phases were separated and the aqueous phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with hexane yielded 750 mg 5-Bromo-1-(4-fluoro-phenyl)-3-methyl-1H-indole as colorless solid, mp 97-98° C., MS: 303(M, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:20][CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCBr)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of 5.00 g (18.2 mmol) tert-butyl N-(tert-butoxycarbonyl)-L-homoserinate (prepared according to J. Org. Chem. 1988, 53, 1900-1903), 3.23 g N-bromo succinimide (18.2 mmol), and 6.16 g polymer bound triphenylphosphine (loading approx. 3 mmol/g, approx. 18.5 mmol) in dichloromethane (60 mL) was stirred overnight at room temperature. All solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (2.5→25% ethyl acetate in hexane) to give 2.56 g of the title compound (38% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].S(O)(O)(=O)=O.[CH3:32][N:33]([CH3:37])[C:34]([NH2:36])=[NH:35].[O-]CC.[Na+].C(O)C>C(O)C>[CH3:32][N:33]([CH3:37])[C:34]1[NH:36][C:17](=[O:18])[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:35]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: CN(C)C(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(N(C)C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
To a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (6.41 g) and N,N-dimethylguanidine sulfate (5.0 g) in ethanol (100 mL) was added 20% sodium ethoxide-ethanol solution (11 mL), and the mixture was heated under reflux for 24 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was washed with water and diethyl ether to give the title compound (2.06 g, 30%) as a pale-yellow solid.
Reaction SMILES: CN(C)C[CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C([Li])CCC.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29]CCl>CCOCC.CCCCCC>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2
Reactant: CN(C)CCC1Sc2ccccc2Sc2ccccc21
Reactant: CN(C)CCCCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(C)CCCC1Sc2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.10 g 11H-dibenzo(b,e)-1,4-dithiepin (of example 14, reference given) in 50 ml of ether was stirred and treated dropwise with 10 ml of 15% n-butyllithium solution in hexane for 15 minutes in a nitrogen atmosphere. The mixture was stirred for another 30 minutes at room temperature. It was then treated dropwise with 10 ml of 3-dimethylaminopropyl chloride, the mixture stirred for 4 hours and washed with water. The basic product was then extracted with dilute hydrochloric acid, the acid layer made alkaline with aqueous ammonia and the base extracted with ether. Processing of the extract yielded 3.7 g for oily base which was chromatographed on a column of 200 g neutral of aluminium oxide (activity II). A small amount of less polar impurities was initially eluted with benzene which then eluted 2.89 g of a homogeneous oily base which was converted by neutralization with oxalic acid to the hydrogen oxalate, m.p. 181°-182° C. (ethanol).