Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:8][C:7]=2[C:18]2[C:19]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([CH3:35])=[C:24]([C:36](O)=[O:37])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:13][CH2:14][CH2:15][O:16]3)=[CH:8][C:7]=2[C:18]2[C:19]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:25]([CH3:35])=[C:24]([C:36]([NH:39][CH:40]4[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]4)=[O:37])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c13) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH3:9])=[C:6]([CH2:24][CH2:25][CH3:26])[N:5]2[N:27]=[CH:28][N:29]=[C:4]2[N:3]1[CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1.O1CCCC1.[BH4-].[Na+]>CO>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([N:3]2[C:2](=[O:1])[C:7]([CH:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH3:9])=[C:6]([CH2:24][CH2:25][CH3:26])[N:5]3[N:27]=[CH:28][N:29]=[C:4]23)[CH2:31][CH2:32]1
Reactant: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4′-{1-[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile (1.38 g), tetrahydrofuran (15 mL) and methanol (10 mL) was added sodium borohydride (0.50 g) at 0° C., and the mixture was stirred at room temperature for 30 min. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.24 g, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[N:17][OH:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)=NO
Yield: 47.8 %

Procedure:
103.14 g (0.5 mole) 2-oxo-4-phenyl butyric acid ethyl ester, 34.75 g (0.5 mole) hydroxylamine hydrochloride, 104 ml (0.75 mole) triethylamine and 500 ml ethanol were agitated overnight at room temperature. The batch was then evaporated to dryness and the residue taken up in 700 ml methyl-tert-butyl ether. After washing with 200 ml water, 200 ml 0.2N hydrochloric acid and 100 ml water, the organic phase was evaporated to dryness and the residue recrystallized after filtration from 170 ml toluene. 52.9 g (48%) 2-hydroxyimino-4-phenyl butyric acid ethyl ester were isolated in the form of colorless crystals. A 1H-NMR spectrum corroborated the suggested structure.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[C:25]1([CH:31]([NH2:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:32]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:38][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: NC(c1ccccc1)c1ccccc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(c4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 82 %

Procedure:
The title compound was prepared in a yield of 82% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and diphenylmethylamine.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15]N)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:4].Cl.O1CCOCC1.N(OCCC(C)C)=O.[N-]=[N+]=[N-].N[C@H:46]([C:54]([NH:56][C@H:57]([C:60]([NH:62][C@H:63]([C:79]([NH:81][C@H:82]([C:88]([OH:90])=[O:89])[CH2:83][CH2:84][C:85](=[O:87])[OH:86])=[O:80])[CH2:64][CH2:65][CH2:66][CH2:67][NH:68][S:69]([C:72]1[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=1)(=[O:71])=[O:70])=[O:61])[CH2:58][OH:59])=[O:55])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:53])[NH2:52]>CN(C)C=O.C(N(CC)CC)C>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:46]([C:54]([NH:56][C@H:57]([C:60]([NH:62][C@H:63]([C:79]([NH:81][C@H:82]([C:88]([OH:90])=[O:89])[CH2:83][CH2:84][C:85](=[O:86])[OH:87])=[O:80])[CH2:64][CH2:65][CH2:66][CH2:67][NH:68][S:69]([C:72]1[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=1)(=[O:71])=[O:70])=[O:61])[CH2:58][OH:59])=[O:55])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:52])[NH2:53])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:4]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)C(=O)NN
Agent: CC(C)CCON=O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
1.03 Grams of Z-Ser-Leu-NHNH2 was dissolved in 15 ml of dimethylformamide, then 1.41 ml of 6N-hydrochloric acid/dioxane was further added thereto, and the mixture was cooled to -15° C., then 0.38 ml of isoamyl nitrite was added under a stirring condition. After the reaction mixture shows a negative reaction in hydrazide test, then a cold solution of 0.40 ml of dimethylformamide with 1.18 ml of triethylamine was added drop by drop in small amounts to neutralize the reaction mixture. This reaction mixture containing the azide was added to 10 ml of a cold dimethylformamide solution containing H-Arg-Ser-Lys(Tos)-Glu-OH obtained in the above-mentioned step 5(a) and 0.66 ml of triethylamine, then whole mixture was stirred at -10° to -15° C. for 2 hours, and at 4° C. for 20 hours. Dimethylformamide was removed by distillation under a reduced pressure and the residue thus obtained was extracted with n-butanol saturated with water and the butanol layer was wahsed 5 times with water being saturated with n-butanol and the solvent was removed by distillation. The residue was solidified by adding ethyl ether, and reprecipitated from methanol-ethyl acetate to obtain 1.92 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([C@@H:28]([OH:30])[CH3:29])[CH2:24][CH2:23]1>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([OH:30])[CH3:29])=[CH:24][CH:23]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Reactant: C[C@H](O)C1CCC(CN)CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc([C@H](C)O)cc2)c1

Procedure:
Prepared from 2-(3-Acetyl-phenoxy)-nicotinic acid and (S)-(−)-1-(4-Aminomethyl-cyclohexyl)-ethanol. mp 102-4° C. αD (CHCl3) −13.8°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.1 %

Procedure:
To a pre-stirred solution of 4-bromo-2-fluorobenzaldehyde (1.82 g, 9.0 mmol) and piperidine (0.97 mL, 9.9 mmol) in DCM (40 mL) at 0° C. was added sodium triacetoxyborohydride (2.85 g, 13.4 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and stirred for an additional 14 h. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (75 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (2.6 g, 84%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.33-7.17 (m, 3H), 3.49 (d, J=1.6 Hz, 2H), 2.43-2.33 (m, 4H), 1.61-1.53 (m, 4H), 1.46-1.38 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(N(CC)CC)C.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.C(OCC)(=O)C>CN(C=O)C>[CH3:18][CH:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH2:8])[CH2:24]1
Reactant: CC1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CN(c2ccccc2N)CCN1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Fluoronitrobenzene (7.1 g, 50 mmol) was dissolved in DMF (100 mL) containing triethylamine (10 g, 100 mmol) and placed under a nitrogen atmosphere. To the solution was added 2-methyl-piperazine (5.5 g, 55 mmol). The reaction was heated to 80° C. for 16 hours. The reaction was allowed to cool to room temperature before the solvent was reduced to half volume in vacuo. Ethyl acetate (200 mL) and ice-water (250 mL) were added to the solution and the product was extracted with diethyether (2×200 mL). The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate (2×200 mL). The organic phases were combined, washed with saturated brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The product (10.5 g) was dissolved in ethanol (250 mL). Palladium on charcoal catalyst (10% w/w, 2.2 g) was added to the solution and the solution was hydrogenated in a Parr apparatus at 3 bar for 3 hours. The solution was filtered and the solvents evaporated in vacuo to give the aniline product. Yield (8.0 g, 83%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]([C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]([C:29]34[CH2:30][CH:31]5[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]5)[CH2:36]3)[CH2:38]4)=[O:28])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C(OCCCBr)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)C12CC3CC(CC(C3)C1)C2

Procedure:
To a stirred solution of 3-bromopropanol (5.5 g, 0.04 mol) in 50 mL of methylene chloride, adamantane-1-carboxylic acid chloride (5.6 g, 0.02 mol) and triethylamine (4 g, 0.04 mol) were added. The reaction mixture was stirred at room temperature overnight, the methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 12 g of the intermediate adamantane-1-carboxylic acid bromopropyl ester. The title compound was prepared by stirring 4-[bis(4-fluorophenyl)-methylene]piperidine (2 g, 0.07 mol), adamantane-1-carboxylic acid bromo-propyl ester (2.1 g, 0.007 mol) and triethylamine (1 g, 0.01 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf =0.7 in 30% ethanol/ethylacetate system) was separated and converted to the hydrochloride salt (0.6 g, 16% yield), mp. 267°-269° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].[C:20]([OH:23])(=O)[CH3:21].[CH2:24](O)[CH3:25]>[Zn]>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:20]([C:21]2[C:24]3[C:25](=[CH:8][CH:3]=[CH:4][CH:5]=3)[N:15]=[CH:10][CH:9]=2)=[O:23])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CC(=O)O
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2[N+](=O)[O-])cc1OC
Reactant: CCO
Agent: [Zn]
Product: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccnc3ccccc23)cc1OC

Procedure:
125 g of (+/−)-cis-1,2-dimethoxy-4-(2-nitrocyclohexyl)benzene and 120 g of zinc powder or granules are suspended in 1300 ml of ethanol. 220 ml of acetic acid are added dropwise at boiling heat. The precipitate is filtered off with suction and washed with ethanol, and the filtrate is concentrated under reduced pressure. The residue is taken up in hydrochloric acid and extracted with toluene. The aqueous phase is rendered alkaline using 50% strength sodium hydroxide solution, the precipitate is filtered off with suction and the filtrate is extracted with toluene. The organic phase is dried using sodium sulfate and concentrated. 98 g of the title compound are obtained as a crystallizing oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:23][O:22][C:10]2=[CH:11][CH:12]=[C:13]3[C:17]([N:16]([CH2:18][CH:19](O)[CH3:20])[N:15]=[CH:14]3)=[C:9]2[CH2:8]1)[CH3:5])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>C1COCC1.CS(C)=O>[N:40]([CH:19]([CH3:20])[CH2:18][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]3[O:22][CH2:23][CH:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:8][C:9]3=2)[CH:14]=[N:15]1)=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(C)OC1COc2ccc3cnn(CC(C)O)c3c2C1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(C)OC1COc2ccc3cnn(CC(C)N=[N+]=[N-])c3c2C1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To solution of the product from Step G (0.52 g, 1.6 mmol) and triethylamine (1.12 mL, 8.1 mmol) in anhydrous THF (75 ml) at 0° C. was added methanesulfonic anhydride (0.71 g, 4.05 mmol). The mixture was stirred for 20 min and sodium azide (2.11 g, 32.4 mmol) was added along with DMSO (20 mL). The THF was removed (in vacuo) and the reaction mixture was heated at 90° C. for 3 h. The mixture was cooled, poured into a saturated solution of sodium bicarbonate (150 mL), and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), and evaporated to a residue that was purified by chromatography (silica, 10% EtOAc/hexane) to give an oil (0.40 g, 72%): LC/MS (+APCI) mz 346 (M+H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:14][O:15][NH:16][CH3:17].C(N(CC)CC)C>>[CH3:17][N:16]([O:15][CH3:14])[C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CNOC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A flask is charged with nicotinic acid (5.0 g, 40.6 mmol). Thionyl chloride (30.0 mL) is added and the reaction is refluxed for 1 h. It is then cooled to room temperature and concentrated in vacuo. The residue is dissolved in anhydrous dichloromethane (30 mL) and O,N-dimethyl-hydroxylamine (4.35 g, 44.0 mmol) is added, followed by addition of triethylamine (14.15 g, 100.0 mmol). The reaction mixture is stirred at room temperature for 1.5 h. It is then washed with water and the aqueous phase is extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and concentrated in vacuo to afford N-methyl-N-methoxy-nicotinamide as a brown oil. MS (ESI) m/z 167.0 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17]C2C=CC(C(Cl)=O)=CC=2)=[CH:15][CH:14]=1.[OH-].[NH4+:30].[O:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:4][C:3]2[CH:2]=[CH:11][C:34]([C:35]([NH2:30])=[O:31])=[CH:33][CH:32]=2)=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 4-(4-(2-quinolinylmethyloxy)benzyl)-benzoyl chloride (0.05 mol) in tetrahydrofuran (300 ml) is added to a concentrated ammonium hydroxide (25 ml) solution and the reaction stirred overnight. The reaction mixture is evaporated and partitioned between ethyl acetate and water. The ethyl acetate fraction is dried and evaporated to give 4-(4-(2-quinolinylmethyloxy)styryl)benzamide.
Reaction SMILES: CS[C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[N:13][CH:12]=[CH:11]3)=[N:5][N:4]=1.O[O:19][S:20]([O-:22])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+].[CH3:31]O>>[CH3:31][S:20]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[N:13][CH:12]=[CH:11]3)=[N:5][N:4]=1)(=[O:22])=[O:19]
Reactant: CSc1nnc(-c2ccc3cnccc3c2)s1
Reactant: O=S([O-])OO
Reactant: CO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Product: CS(=O)(=O)c1nnc(-c2ccc3cnccc3c2)s1
Yield: 60 %

Procedure:
To a 25 mL round bottom flask was added 6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)isoquinoline (0.28 g, 1.1 mmol), Oxone® monopersulfate (2.7 g, 4.3 mmol) and 10 mL of MeOH. The reaction mixture was heated at reflux for 4 hours. Sodium thiosulfate solution (25 mL, 1 M) was added to the mixture. The mixture was then extracted with EtOAc (3×30 mL). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with a gradient of 0 to 90% EtOAc in hexanes) to provide 6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)isoquinoline (0.19 g, 60%) as a yellow solid. LCMS (M+H) 292 calc. for C12H10N3O2S2 292.0. 1H NMR (400 MHz, CD3OD): δ ppm 2.77-2.79 (m, 3H), 7.19 (d, J=5.67 Hz, 1H), 7.49-7.53 (m, 1H), 7.54-7.58 (m, 1H), 7.78 (d, J=5.87 Hz, 1H), 7.92 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH:38]([NH:42]C(=O)OC(C)(C)C)[CH2:37]1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH2:42])[CH2:37]2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-c2csc3c(/C=C/CN4CCCC(N)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 19.6 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (100 mg, 0.207 mmol) and tert-butyl piperidin-3-ylcarbamate (124 mg, 0.621 mmol), were reacted according to General Procedure B. The crude product (137 mg, 0.206 mmol) was dissolved in methanol (1 mL) and treated with 6.0 M hydrochloric acid in 1,4 dioxane (0.514 mL, 2.06 mmol) and heated to 55 degrees Celsius for 20 hours. The mixture was cooled to room temperature then 1M sodium carbonate solution (5 mL) was added and product was extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified via HPLC preparation to furnish the title compound as an ivory powder (23.0 mg, 0.0406 mmol): LCMS (Conditions a): MH−=565 RT=3.35 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.45 (1H), 7.91 (2H), 7.65 (1H), 7.28 (3H), 7.10 (3H), 7.01 (1H), 6.64 (1H), 6.15 (1H), 5.59 (1H), 3.71 (3H), 3.85 (3H), 3.52 (1H), 3.14 (2H), 2.89 (1H), 2.78 (1H), 2.62 (1H), 2.16 (1H), 2.03 (1H), 1.66 (1H), 1.42 (1H), 1.15 (1H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.CS(O[CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54]/[C:53]/1=[CH:58]\[C:59]([O:61][CH3:62])=[O:60])(=O)=O>CN(C)C=O>[CH3:62][O:61][C:59](/[CH:58]=[C:53]1/[CH:52]([N:3]2[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)=[N:4]2)[CH2:57][CH2:56][CH2:55][CH2:54]/1)=[O:60]
Reactant: COC(=O)/C=C1\CCCCC1OS(C)(=O)=O
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C1\CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (271 mg) in N,N-dimethylformamide (6 ml) was added potassium tert-butoxide (111 mg) and 18-crown-6 (24.8 mg) at 5° C. To this solution was added a solution of (E)-1-methylsulfonyloxy-2-methoxycarbonylmethylenecyclohexane (467 mg) in N,N-dimethylformamide (2 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then heated at 110 to 125° C. for 7 hours. The reaction mixture was poured into ice water (30 ml) and extracted with ethyl acetate (20 ml×2). The combined extracts were washed with water (20 ml) and brine (20 ml), dried over anhydrous magnesium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on SiO2 using a mixture of dichloromethane and ethyl acetate (20:1) as an eluant to give colorless crystals of (E)-3-[2-(2-methoxycarbonylmethylenecyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (191.4 mg).