Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH2:2]([O:4][C:5]([C:7]1[C:16]([Cl:17])=[CH:15][C:14]2[C:9](=[C:10]([C:18]#N)[CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])[CH3:3].CC(O)=[O:22]>[Ni].N1C=CC=CC=1>[CH2:2]([O:4][C:5]([C:7]1[C:16]([Cl:17])=[CH:15][C:14]2[C:9](=[C:10]([CH:18]=[O:22])[CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])[CH3:3]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc2c(C#N)cccc2cc1Cl
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc2c(C=O)cccc2cc1Cl
Temperature: 125 °C

Procedure:
NaH2PO2×H2O (2.12 g, 20.02 mmol, 8.0 equiv) and Raney nickel (1.50 g) were added at room temperature to a solution of 3-chloro-8-cyano-naphthalene-2-carboxylic acid ethyl ester (0.65 g, 2.50 mmol) in pyridine (16 ml)/AcOH (8 ml)/H2O (8 ml). The heterogeneous mixture was heated to 125° C. for 2 hours. After cooling and filtering off the Raney nickel catalyst, the reaction mixture was diluted with water (100 ml). After extraction with EtOAc (2×400 ml), the combined organic layers were washed with brine (2×50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 90:10) to afford the title compound (350 mg, 53%, inseparable 1:1.5 mixture of regioisomers A:B) as a white solid. 1H NMR (400 MHz, CDCl3): δ=10.35 (s, 1H isomer B), 10.33 (s, 1H isomer A), 9.70 (s, 1H isomer B), 9.41 (s, 1H isomer A), 8.39 (s, 1H isomer A), 8.14 (d, J=8.4 Hz, 1H isomer A). 8.08 (dd, J=7.1/1.2 Hz, 1H isomer B), 8.04-8.01 (m, 1H isomer A+1H isomer B), 7.99 (1H isomer B), 7.77-7.70 (m, 1H isomer A+1H isomer B), 4.48 (q, J=7.1 Hz, 2H isomer B), 4.47 (q, J=7.1 Hz, 2H isomer A), 1.46 (t, J=7.1 Hz, 3H isomer B), 1.45 (t, J=7.1 Hz, 3H isomer A). MS (ES+): 263 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31](=[O:33])[CH3:32])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3,4-difluorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 403, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:29]=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[C:6]2[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:5]1=2)(=[O:3])[CH3:2].[ClH:48]>O1CCOCC1.CCOCC>[ClH:48].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:29]=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[C:6]2[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccccc2)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2cc(-c3ccccc3)ccc2OC)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 87 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (37 mg, 57.8 μmol) in 4 M HCl in dioxane (289 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-1-((4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (29.0 mg, 87%) as a white solid. MS m/z 540 (MH)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:9][N:8]=1.[CH3:34][NH2:35].C([O-])([O-])=O.[K+].[K+]>CCOCC>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:10]2[S:11][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:35][CH3:34])=[N:8][N:9]=2)(=[O:15])=[O:14])=[CH:17][CH:18]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCBr)s2)cc1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCNC)s2)cc1
Yield: 61 %

Procedure:
A mixture of N-(5-(5-bromopentyl)-1,3,4-thiadiazol-2-yl)-4-dodecylbenzenesulfonamide (100 mg, 0.18 mmol), CH3NH2 (0.42 mL, 40% solution in water, 5.4 mmol), K2CO3 (25 mg, 0.18 mmol), and KI (30 mg, 0.18 mmol) was heated at reflux for 2 d. The reaction mixture was diluted with ether (50 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography over silica gel 60 (70-230 mesh) eluted with CH2Cl2:methanol 2:3 to give the product as a solid, mp 158-160° C., in 61% yield (56 mg, 0.11 mmol). 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3, J=7.2 Hz), 1.25-1.36 (m, 18), 1.53-1.67 (m, 8), 2.57-2.61 (m, 5), 2.68 (t, 2, J=7.2 Hz), 2.96 (t, 2, J=6.9 Hz), 7.20 (d, 2, J=8.4 Hz), 7.75 (d, 2, J=8.1 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.7, 25.5, 28.3, 29.3, 29.4, 29.5, 29.7, 30.5, 31.2, 31.9, 33.1, 35.8, 60.0, 126.1, 128.5, 140.7, 146.7, 163.7, 170.7; HRMS (ESI+, m/z) calculated for C26H45N4O2S2 509.2984, observed 509.2972 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH3:21][O:22][C:23]([N:25]=[C:26]=[S:27])=[O:24]>>[CH3:21][O:22][C:23]([NH:25][C:26](=[S:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])=[O:24]
Reactant: Nc1ccc(OCCOc2ccccc2)cc1[N+](=O)[O-]
Reactant: COC(=O)N=C=S
Product: COC(=O)NC(=S)Nc1ccc(OCCOc2ccccc2)cc1[N+](=O)[O-]

Procedure:
The 1-amino-2-nitro-4-(2-phenoxyethoxy)benzene so obtained is treated with methoxycarbonyl isothiocyanate (as per Example XL) to afford 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-(2-phenoxyethoxy)benzene which is reduced with sodium hydrosulfite (as per Example XXI) or iron-ferrous sulfate (as per Example VII) to afford 1-(3-methoxycarbonyl-2-thioureido)-2-amino-4-(2-phenoxyethoxy)benzene. The latter compound is further reacted with another equivalent of methoxycarbonyl isothiocyanate to afford 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-(2-phenoxyethoxy)benzene.
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[Br:1][C:2]1[C:8]([C:9]([F:10])([F:11])[F:12])=[CH:7][C:5]([NH:6][C:14](=[O:16])[CH3:15])=[C:4]([F:13])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1F
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of compound 22 (3.6 g, 14 mmol), acetic anhydride (8 mL) and pyridine (0.1 mL) was stirred at room temperature for 1 h, then concentrated in vacuo. The residue was added ice and sodium bicarbonate (until pH=7). The resulted mixture was extracted with EtOAc. The organic layers were combined, washed by brine, dried over Na2SO4, filtered and concentrated to give the title compound 23 (3.5 g, 83%). 1H NMR (400 MHz, CDCl3) δ8.79 (d, 1H, J=7.8 Hz), 7.46 (d, 1H, J=10.0 Hz), 7.38 (br s, 1H), 2.24 (s, 3H).
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(O)C>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:20][CH2:19]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCCCCCN(C(C)=O)c1ccccc1OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCN(C(C)=O)c1ccccc1OC1CCN(Cc2ccccc2)CC1
Yield: 68.8 %

Procedure:
To a solution of 4-(N-acetyl-N-hexylaminophenyloxy)piperidine (1.4 g) in ethanol (10 ml) were added potassium carbonate (1.2 g) and benzyl chloride (0.54 g) and the mixture was heated under reflux overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate (50 ml×3). The combined extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride/methanol =10/1 (v/v)) to obtain 4-(N-acetyl-N-hexylaminophenyloxy)-1-phenylmethylpiperidine (1.2 g) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:7])=[CH:23][CH:24]=1)[CH3:26]
Reactant: CCN(CC)CCCCl
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
A mixture of 6.2 g. (19.7 mmol.) of 3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 2.95 g. (19.7 mmol.) of 3-diethylaminopropyl chloride and 10.9 g. (0.079 mol.) of potassium carbonate in 300 ml. of acetone is refluxed for 12 hours. After cooling, the mixture is filtered and the filtrate is concentrated to give the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([N:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24].CCOC(C)=O>CN(C=O)C>[O:24]=[C:23]([N:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:22][NH:14][C:9]1[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(CBr)N1CCCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1ccccc1Nc1ccccc1)N1CCCCc2ccccc21
Yield: 99.2 %

Procedure:
To a stirring solution of N-phenyl-o-phenylene diamine (10 g, 54.3 mM) in 100 ml of DMF at RT was added K2CO3 (8.25 g, 60 mM) followed by 1-(bromoacetyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (14.56 g 54.3 mM). The resulting mixture was stirred at RT until TLC (Hex:AcOEt 3:1) showed completion of reaction. The mixture was filtered to remove the K2CO3 and then diluted with 800 mL of EtOAc and 200 mL of Et2O. This solution was washed successively with H2O (2×400 mL), brine (1×400 mL), 1 N HCl (2×400 mL), and H2O (1×400 mL), and the organics dried (MgSO4) and concentrated to give a greenish-black oil. The resultant oil was purified by silica gel flash column chromatography using hexane/EtOAc4/1 and the combined filtrates evaporated in vacuo to give 20 g of product. 1H NMR (300 MHz, CDCl3) 1.25–1.40 (m, 1H), 1.66–2.00 (m, 3H), 2.55.2.75 (m, 2H), 2.88 (t, J=13 Hz, 1H), 3.54(d, J=17 Hz, 1H), 4.10 (d, J=17 Hz, 1H), 4.57 (m, 1H), 6.80–7.80 (m, 12H), 7.47 (m, 1H).
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(O)(C)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:31][C:28]([CH:29]=[C:6]3[CH2:5][CH2:4][CH2:3][N:2]=[C:7]3[C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Agent: [Cl-]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(-c2ccc(C=C3CCCN=C3c3cccnc3)o2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (95 mg, 0.38 mmol) and 5-(4-nitrophenyl)furfural (99 mg, 0.46 mmol) were combined in a reaction vessel and treated with isopropanol (6 mL). The reaction vessel was sealed and the reaction was heated to 80° C. with stirring overnight. The reaction was then cooled to room temperature, concentrated under reduced pressure and treated with saturated NaHCO3(aq). This mixture was then extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with 10.5:7:7:1:0.1 hexane:MTBE:CH2Cl2:MeOH:NH4OH (1 liter). One sample was recovered that appeared to be highly crystalline. This material was re-crystallized from hot methanol. The crystals were recovered by vacuum filtration, washed with isopropanol then dried under vacuum giving 50 mg (36%) of an orange crystalline solid. LC-MS: RT=5.16 min, [M+H]+=360.0.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]=1[CH3:13].Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[NH:26][N:25]=[C:24]([CH:27]3[CH2:29][CH2:28]3)[CH:23]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:27]1([C:24]2[NH:25][N:26]=[C:22]([NH:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:2]([CH3:1])[CH2:3][C:4]4[CH:12]=[CH:11][C:7]5[NH:8][CH:9]=[N:10][C:6]=5[C:5]=4[CH3:13])[N:20]=3)[CH:23]=2)[CH2:29][CH2:28]1
Reactant: CNCc1ccc2[nH]cnc2c1C
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)c2nccc(Nc3cc(C4CC4)[nH]n3)n2)ccc2[nH]cnc12
Temperature: 120 °C

Procedure:
A tube was charged with 264 (40 mg, 0.23 mmol), 53 (100 mg, 0.57 mmol), and DIPEA (0.3 ml) in IPA (3 mL), degassed, sealed and heated at 120° C. overnight. After removal of the solvent in vacuo, the crude was purified by preparative HPLC to afford 25 mg (29%) of I-95 as white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])C>CC#N>[N+:22]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([O-:24])=[O:23]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-amino-1-piperidinecarboxylate (3.53 g, 20.5 mmol) and 4-ethoxy-3-nitropyridine (3.65 g, 21/7 mmol) in CH3CN (25 mL) was heated at reflux for 40 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an orange syrup which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[NH2:12][OH:13].[OH-].[Na+]>CCO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2/[CH:10]=[N:12]\[OH:13])[CH:3]=[CH:2]1
Reactant: NO
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1cccc2cc[nH]c12
Yield: 80 %

Procedure:
1H-indole-7-carbaldehyde (1 g, 6.9 mmol) in EtOH (30 mL), hydroxylamine (527 mg, 7.6 mmol) in water (10 mL) was added followed by 50% NaOH (1.38 g in 1.38 mL water) was added. After refluxing for 2 h, ethanol was removed under reduced pressure. Resultant slurry was extracted with ethylacetate. Organic layer was washed with water, brine and dried. Crude residue was column chromatographed on a silica gel eluting with (30% EtOAc/hexanes) to afford (Z)-1H-indole-7-carbaldehyde oxime in 80% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)C(Cl)=O)([O-:26])=[O:25]>C(Cl)(Cl)Cl>[CH3:12][O:11][C:9]1[C:8]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:34]2[CH:33]=[CH:29][CH:28]=[C:27]([N+:24]([O-:26])=[O:25])[CH:35]=2)[CH:10]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COCCOc1cc(C(N)=O)c(N)cc1OC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COCCOc1cc(C(N)=O)c(Nc2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-amino-4-methoxy-5-(2-methoxyethoxyl)benzamide (1.78 g, 7.40 mmol) and pyridine (2.40 mL, 29.6 mmol) in CHCl3 (40 mL) was added 3-nitrobenzoyl chloride (1.44 g, 7.8 mmol). The mixture was stirred at RT for 2.5 h upon which the mixture was concentrated in vacuo to give the desired product, which was used directly in the next step without purification.
Reaction SMILES: [Bi](Cl)(Cl)Cl.[I-].[Na+].[C:7](Cl)(=[O:9])[CH3:8].[CH2:11]([O:13][C:14]([C:16]1[C:17]2[C:32]([O:33][Si](C)(C)C)=[CH:31][CH2:30][CH2:29][CH2:28][C:18]=2[N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)=[O:15])[CH3:12]>C(Cl)Cl.CCOCC>[CH2:11]([O:13][C:14]([C:16]1[C:17]2[C:32](=[O:33])[CH:31]([C:7](=[O:9])[CH3:8])[CH2:30][CH2:29][CH2:28][C:18]=2[N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCCC2
Reactant: CC(=O)Cl
Agent: Cl[Bi](Cl)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(C(C)=O)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Bismuth (III) chloride (0.1 mmol) and sodium iodide (0.3 mmol) are transferred to a dried flask under nitrogen and 5 mL of a mixture of CH2Cl2/ether (9/1) is added by a syringe. This is followed by the addition of acetyl chloride (2.2 mmol) and the suspension is stirred for 5 min at RT. 4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2 mmol) in 5 mL of the same solvent mixture is added. After 2 hours at RT, the mixture is quenched with 20 mL saturated NaHCO3 solution and extracted several times with CH2Cl2. The organic layers are combined, dried over Na2SO4 and evaporated in vacuo yielding 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester as an oil (86%). LRMS 363.4 found (M+1) 364.2
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.N1C=CC=CC=1.S(Cl)([Cl:28])(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:28])[S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1sccc1Cl)C2
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccnc2c1C(=O)CC(c1sc(Cl)cc1Cl)C2
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of 7-(3-chlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.74 g) in ethyl acetate (10 ml) were added pyridine (0.21 g) and sulfuryl chloride (1.1 g) at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction solution was added ethyl acetate, and the mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give 7-(3,5-dichlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.56 g).
Reaction SMILES: [F:1][C:2]([F:35])([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1)[CH:3]([F:25])[O:4][C:5]([F:24])([F:23])[C:6]([F:22])([O:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:7]([F:10])([F:9])[F:8].[C:36](OC)(=[O:40])[C:37]([CH3:39])=[CH2:38]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[C:36]([O:34][CH2:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:2]([F:35])([F:1])[CH:3]([F:25])[O:4][C:5]([F:23])([F:24])[C:6]([F:22])([O:11][C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:17])[F:16])[C:7]([F:10])([F:9])[F:8])=[CH:32][CH:31]=1)(=[O:40])[C:37]([CH3:39])=[CH2:38]
Reactant: OCc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Reactant: C=C(C)C(=O)OC
Agent: [Ti]
Solvent: CCCCO
Product: C=C(C)C(=O)OCc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1

Procedure:
In the dry box, the (4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)phenyl)methanol (36.5 g, 0.656 mol) and methyl methacrylate (40.0 g, 0.40 mol) were added to a round bottom flask equipped with a stirrer. Titanium(iv) n-butoxide (0.50 mL) was then added to the round bottom flask. The reaction was placed in an oil bath and heated to reflux over about 3 hours. Then the reaction product was distilled to remove excess methyl methacrylate. The content was analyzed by proton NMR and shown to be 4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzyl methacrylate.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH:11]([CH3:19])[CH2:12][CH2:13][C:14]([O:16]CC)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[S:10][CH:11]([CH3:19])[CH2:12][CH2:13][C:14]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:16]
Reactant: CCOC(=O)CCC(C)Sc1nc2ccccc2[nH]1
Reactant: C1COCCN1
Product: CC(CCC(=O)N1CCOCC1)Sc1nc2ccccc2[nH]1
Yield: 57.6 %

Procedure:
0.56 g of ethyl 4-(2-benzimidazolylthio)valerate and 0.53 g of morpholine were heated at 100° C. for 20 hours. The reaction mixture was applied without treatment to a silica gel column for purification (methanol:methylene chloride=1:10), and 0.37 g of the title compound was obtained as solid (yield: 58%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](OCC)(OCC)(OCC)[CH3:11]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][CH2:2][C:3]12[CH2:8][O:9][C:10]([CH3:11])([O:7][CH2:6]1)[O:5][CH2:4]2
Reactant: CCOC(C)(OCC)OCC
Reactant: OCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC12OCC(CO)(CO1)CO2
Temperature: 125 °C
Yield: 93 %

Procedure:
To a suspension of pentaerythritol (13.6 g, 0.100 mol) in 10 mL of toluene was added freshly distilled triethyl orthoacetate (16.2 g. 18.3 mL, 0.100 mol) and p-toluenesulfonic acid monohydrate (50 mg). The mixture was slowly heated in an oil bath and ethanol was distilled from the mixture over a period of 12 hrs. After removal of the ethanol, the bath temperature was raised to 125° C. and toluene was distilled off until the solution was homogeneous (about 30 mL). The residue was sublimed (bulb to bulb, ~130--C, 2.5 mmHg) to give 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.21octane (15.0 g, 0.093 mol, 93%).