Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([N+:13]([O-])=O)[CH:5]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:28]([N:35]1[C:39](=[O:40])[C:38](=[C:41]2[N:45]([CH3:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[S:42]2)[S:37][CH2+:36]1SC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([N:13]=[C:36]2[N:35]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:39](=[O:40])[C:38](=[C:41]3[N:45]([CH3:46])[C:44]4[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=4[S:42]3)[S:37]2)[CH:5]=1
Reactant: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(=O)OC)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-ethylamino-3-nitrobenzoic acid methyl ester was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.73 (1H, dd), 7.65 (1H, d), 7.52 (1H, dd), 7.45–7.49 (2H, m), 7.27–7.38 (4H, m), 7.18 (1H, m), 7.06 (1H, d), 6.52 (1H, d), 5.19 (2H, s), 4.14 (1H, br t), 3.85 (3H, s), 3.78 (3H, s), 3.04 (2H, m), 1.04 (3H, t); MS(ESI): 531 (MH+).
Reaction SMILES: [C:1]12(C3C(=C)C=CC=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.[CH2:23](OCC)C>O>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[C:18]1[CH2:23][CH:21]=[CH:20][CH:19]=1)[CH2:9]2
Reactant: C=C1C=CC=C1C12CC3CC(CC(C3)C1)C2
Reactant: CCOCC
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: C1=CCC(C2C3CC4CC(C3)CC2C4)=C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A 500 mL argon-purged round bottom flask was charged with LiA1H4 (8.20 g, 216 mmol) and 100 mL tetrahydrofuran. Adamantylfulvene (30.00 g, 151.3 mmol) was added via solid addition funnel, followed by another 100 mL tetrahydrofuran over 2 minutes at 0° C. After stirring for 22 hours at room temperature, the reaction was cooled to 0° C. and 100 mL water were added dropwise over 60 minutes. Then, 100 mL concentrated aqueous HCl in 300 mL water and 50 mL diethyl ether were added. The organic layer was isolated and the aqueous layer extracted with diethyl ether (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and rotavapped to give 30.30 g of product in quantitative yield. MS (GC-MS) m/z 200.3 (M+).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N>O>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][C:15](=[O:16])[CH2:20][CH2:21]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2noc(N3CCC4(CC3)OCCO4)n2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: O=C1CCN(c2nc(-c3ccccc3)no2)CC1

Procedure:
A mixture of 8-(3-phenyl-[1,2,4]oxadiazol-5-yl)-1,4-dioxa-8-aza-spiro[4.5]decane (660 mg), conc. aqueous HCl (5 mL) and water (5 mL) is kept at room temperature over night. The mixture is basified with conc. aqueous ammonia and the precipitate is filtered off and dissolved in dichloromethane. The resulting solution is dried over Na2SO4 and concentrated in vacuo to give the title compound. TLC: rf=0.33 (silica gel, hexane/ethyl acetate 2:1); Mass spectrum (ESI+): m/z=244 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12](O)[CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:24]1(=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[NH:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:34]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[C@@H:12]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1)[CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(C[C@H](O)c1ccc(C(F)(F)F)c(F)c1)C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C[C@H](c1ccc(C(F)(F)F)c(F)c1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a solution of 262 (0.98 g, 2.91 mmol) and THF (30 mL) cooled to 0° C. was added sequentially isoindoline-1,3-dione (0.470 g, 3.20 mmol) and PPh3 (1.14 g, 4.36 mmol), followed by a solution of DEAD (1.72 mL, 4.36 mmol) and THF (10 mL). The reaction was warmed to RT and stirred overnight. The reaction was concentrated to dryness, Et2O (300 mL) added and the resulting solid was filtered and discarded. The filtrate was then poured into water, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM:MeOH (500:2) to afford 0.99 g (73.1%) of (S)-tert-butyl 2-(1,3-dioxoisoindolin-2-yl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl(methyl)carbamate (264).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][CH3:16])[CH2:10][CH2:9]1)(C)(C)C.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>C(Cl)Cl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:16][O:15][CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]1
Reactant: COC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H]1CC[C@H](N)CC1
Reaction time: 1 h

Procedure:
A solution of trans (4-methoxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (1.41 g, 5.80 mmol) in DCM (12 mL) was treated with trifluoroacetic acid (4 mL). The mixture was stirred for 1 hour then concentrated under vacuum. The residue was taken into ether and concentrated under vacuum a total of five times to afford 1.88 g of crude trans 4-methoxymethyl-cyclohexylamine trifluoroacetic acid salt as a colourless residue. This was not purified further. 1H NMR (400 MHz, CDCl3): δ 7.48 (br s, 3H), 3.34 (s, 3H), 3.22 (d, 2H), 3.15-3.00 (m, 1H), 2.11-2.00 (m, 2H), 1.94-1.83 (m, 2H), 1.65-1.50 (m, 1H), 1.46-1.31 (m, 2H), 1.13-0.96 (m, 2H).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[CH3:14][C:15]1([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]([NH2:21])[CH2:16]1>CC(C)=O>[CH3:14][C:15]1([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:11]([NH2:12])=[S:10])[CH2:16]1
Reactant: CC1(C)CCCC(N)C1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: CC1(C)CCCC(NC(N)=S)C1
Temperature: 0 °C

Procedure:
59 g (0.42 mol) of benzoyl chloride were added dropwise over the course of 10 minutes to a solution of 33 g (0.44 mol) of ammonium thiocyanate in 100 ml of absolute acetone. The mixture was refluxed for 10 minutes and then 50.8 g (0.40 mol) of 3,3-dimethylcyclohexylamine were added dropwise, and the mixture was refluxed for a further 20 minutes and then stirred into 500 ml of ice-water. The precipitated solid was filtered off with suction, washed with water, dissolved in a hot mixture of 500 ml of 10% strength sodium hydroxide solution and 125 ml of ethanol and refluxed for 30 minutes. The reaction mixture was then diluted with ice-water, and the pH was initially adjusted to 1 with concentrated hydrochloric acid and then to 9 with solid sodium bicarbonate. The resulting precipitate was filtered off with suction, washed with water and dried at 80° C. under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O>C1C=CC=CC=1.CN(C)C=O>[CH:8]([NH:12][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])[C:9]([F:11])=[CH:10][C:2]=1[Cl:1])([CH3:9])[CH3:7]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3.5 g of 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoic acid and 3.4 ml of thionyl chloride in 20 ml of benzene is heated to reflux temperature for 3 hours together with 2 drops of dimethylformamide. The mixture is then evaporated to dryness and the residue is dissolved in 15 ml of dioxan. The solution is added dropwise at room temperature to a solution of 0.7 g of isopropylamine and 1.1 g of pyridine in 15 ml of dioxan and the reaction mixture is stirred at room temperature for 2.5 hours. Subsequently, the mixture is treated with 400 ml of water, extracted twice with 400 ml of ethyl acetate each time, the organic phases are washed twice with 200 ml of 1N hydrochloric acid each time, thereafter twice with 200 ml of saturated sodium chloride solution each time, and the combined organic phases are dried over anhydrous sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with ethyl acetate/n-hexane (1:2) as the eluent. In this manner there is obtained N-isopropyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide which can be recrystallized from ethyl acetate/n-hexane. M.p. 146°-149° C.
Reaction SMILES: C([O:5]OC(C)(C)C)(C)(C)C.[Se](=O)=O.[C:14]([CH:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([CH3:35])[CH:29]=[C:28]3[C:36]([F:39])([F:38])[F:37])[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1>[C:14]([C@H:18]1[CH2:23][CH2:22][C@H:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([CH:35]=[O:5])[CH:29]=[C:28]3[C:36]([F:39])([F:37])[F:38])[CH2:20][CH2:19]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1cc(C(F)(F)F)c2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)cc(C(F)(F)F)c3c2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Di-tert-butyl peroxide (0.186 mL, 1.01 mmol) was added to a suspension of Selenium dioxide (0.252 g, 2.27 mmol) in 1,4-Dioxane (6.0 mL). The mixture was stirred for 30 minutes, then 6-(4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline (0.366 g, 1.00 mmol) was added as a solution in 1,4-Dioxane (2.0 mL). The mixture was sealed and was heated at 50° C. for 20 h. The reaction was filtered through Celite and washed with dioxane. The solvent was evaporated and the residue was purified on silica gel column using 0-20% ethyl acetate in hexanes as eluent. Isolated was (Rf=0.70 in 3:1 hexanes/ethyl acetate) the product (212 mg, 56%). ESI-MS(M+H+): 380.20.
Reaction SMILES: [Na].Cl.Cl.[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][CH:6]=1.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C>C(O)C>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[N:11]=[C:17]([OH:16])[C:18]([C:19]([OH:21])=[O:20])=[CH:24][N:10]=2)=[CH:7][CH:6]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)c1ccc(N)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reaction time: 0.08 h
Yield: 102671.1 %

Procedure:
A solution of 14.8 g (0.642 mmol) of sodium in 750 ml of dry ethanol is stirred at 0° and 44.6 g (0.214 mmol) of 4-aminobenzamidine 2HCl [Shaw and Cooley, J. Am. Chem. Soc., 79, 3561 (1957)] is added. The mixture is stirred 5 minutes under nitrogen and 46.2 g (0.214 mmol) of diethyl ethoxymethylenemalonate is added. After stirring for 30 min, the mixture is refluxed for 4 hr and allowed to stand overnight at room temperature. The salt is filtered and washed with isopropanol. The salt is suspended in 214 ml of 2 N potassium hydroxide and stirred at 70° C. for 4 hr. After treating with a small amount of charcoal, the filtrate is added to 325 ml of 2 N HCl with stirring. The acid is filtered, washed with water, ethanol, and ether, and dried to give 50.8 g of the title compound, mp 312°-314° C. dec. The product is recrystallized from dimethylacetamide-water to give 44.5 g mp 313°-314° C. dec. ##EQU42##
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].S(O[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)(=O)C.C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH2:17][O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:21][CH:22]=1
Reactant: [O-]CCCN1CCCCC1
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(CCCOCCCN2CCCCC2)cc1
Yield: 75 %

Procedure:
According to the method disclosed in EP-982300, Example 78, sodium 3-piperidinopropanolate (2.127 kg; 12.88 mol), 3-(4-chlorophenyl)propyl mesylate (1.121 kg; 4.51 mol) and 0.322 mol of 15-crown-5 in 4.5 kg of dry toluene were refluxed for 4 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol (90/10)). The obtained oil was distilled in a fractionating equipment at reduced pressure (0.3-0.7 mmHg) and with a heating jacket at 207-210° C. The head fractions and the distilled fraction at 0.001-0.010 mmHg with a jacket temperature of 180-200° C. were collected. The obtained oil (1.0 kg; 3.38 mol) corresponds to 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine. Yield 75%.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][CH2:32][CH2:33][CH:34]=O.C([BH3-])#N.[Na+].Cl>CO.C(OCC)C>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:31][CH2:32][CH2:33][CH3:34])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC=O
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.7 g, 1.7 mmol) was dissolved in dry methanol. Butyric aldehyde (0.153 ml, 1.7 mmol) and sodium cyanoborohydride (0.107 g, 1.7 mmol) was added. A solution of anhydrous hydrogen chloride in diethylether (2 M) was added dropwise until pH 6. The resulting mixture was stirred for 24 hours at room temperature under a nitrogen atmosphere and evaporated in vacuo. Addition of 1M sodium hydroxide (50 ml), extraction of the product with diethylether (2×50 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo gave the title compound as a crude oil (0.644 g). Purification of the crude product on a silica gel column (Eluent: methylene chloride/methanol (19:1)) afforded (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxy-methyl-1-butylpyrrolidine (0.243 g, yield: 30%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[C:9]([CH2:12][C:13](=O)[CH3:14])O[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[N:25]=[C:24]([NH:26][NH2:27])[CH:23]=[CH:22][CH:21]=1)[CH3:18].[Cl:28]C1C=CC=C(OCC)N=1>>[Cl:28][C:1]1[C:2]2[C:11](=[C:6]([CH3:7])[CH:5]=[CH:4][CH:3]=2)[N:10]=[C:9]2[N:26]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH2:17][CH3:18])[N:25]=3)[N:27]=[C:13]([CH3:14])[C:12]=12
Reactant: CC(=O)Cc1nc2c(C)cccc2c(=O)o1
Reactant: CCOc1cccc(Cl)n1
Reactant: CCOc1cccc(NN)n1
Product: CCOc1cccc(-n2nc(C)c3c(Cl)c4cccc(C)c4nc32)n1

Procedure:
Following the procedures described in Reference Example 1-10 and Example 1-34, the title compound was prepared from 8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 6-ethoxy-2-hydrazinopyridine which was separately prepared from 2-chloro-6-ethoxypyridine following the method described in Reference Example 1-9 (62% yield).
Reaction SMILES: [NH:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:2][CH2:3][C:4]#[N:5].N[NH:11][C:12]([NH2:14])=[S:13].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:11][C:12]1[S:13][C:4]([CH2:3][CH2:2][NH:1][CH2:6][CH2:7][C:8]2[S:13][C:12]([NH2:14])=[N:11][N:9]=2)=[N:5][N:14]=1
Reactant: N#CCCNCCC#N
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CCNCCc2nnc(N)s2)s1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A mixture of 3,3′-iminodipropionitrile (1.50 g, 12.18 mmol) and thiosemicarbazide (2.22 g, 24.36 mmol) in TFA (10 mL) was heated at 85 for 4.5 h. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5-(2-((2-(5-amino-1,3,4-thiadiazol-2-yl)ethyl)amino)ethyl)-1,3,4-thiadiazol-2-amine (1005, 1.47 g). 1H NMR (300 MHz, DMSO-d6) δ 6.95 (s, 4H), 2.90 (d, J=6.0 Hz, 4H), 2.83 (d, J=6.3 Hz, 4H).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:18]([C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CCCCCCCCc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCCCCCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 95 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (0.30 g, 0.26 mmol) and p-n-octylphenylboronic acid (1.0 g, 4.3 mmol) were sequentially added to a stirred solution of 4-nitroiodobenzene (0.87 g, 3.5 mmol) in 1,2-dimethoxyethane (13 mL) and aqueous sodium carbonate (2 M, 13 mL) under dry nitrogen. The stirred mixture was heated under reflux overnight and cooled. Water was added and the product was extracted into ether (30 3 mL) and the combined ethereal extracts were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by chromatography using a short silica gel column (hexane:ethyl acetate—5:1 to 2:1] to provide 4′-nitro-4-n-octyl-biphenyl as a yellow oil, which solidified upon standing (1.04 g, 95% yield). The solid was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]([CH3:31])[C:21]([CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:22][N:23]=3)[S:18][C:11]=12)[NH2:5].CC[N:34]([CH:38]([CH3:40])[CH3:39])[CH:35](C)C.ClC(Cl)([O:44]C(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1>C1COCC1>[CH:38]1([NH:34][C:35]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:16]=[C:17]([C:19]5[N:20]([CH3:31])[C:21]([CH2:24][N:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:22][N:23]=5)[S:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)=[O:44])[CH2:39][CH2:40]1
Reactant: Cn1c(CN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: NC1CC1
Solvent: C1CCOC1
Product: Cn1c(CN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc(NC(=O)NC4CC4)cc3F)c2s1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
To a solution of aniline 297 (200 mg, 0.455 mmol) in THF (20 mL) at 0° C. was added DIPEA (0.318 mL, 1.820 mmol) and triphosgene (81 mg, 0.273 mmol). The mixture was stirred at 0° C. for 1 hr before cyclopropylamine (0.160 mL, 2.275 mmol) was added, and was allowed to warm to RT over 1 hr. The mixture was concentrated and purified by Biotage (MeOH/DCM, 0-22%, SNAP 25 g cartridge) to afford title compound 298 (54 mg, 0.103 mmol, 22.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.50 (d, 1H, J=5.5 Hz), 7.89 (s, 1H), 7.70 (dd, 1H, J1=2.3 Hz, J2=13.9 Hz), 7.35 (t, 1H, J=9.0 Hz), 7.18-7.16 (m, 1H), 6.96 (s, 1H), 6.65 (d, 1H, J=5.5 Hz), 6.55-6.54 (m, 1H), 3.91 (s, 3H), 3.55 (t, 4H, J=3.4 Hz), 3.51 (s, 2H), 2.54-2.51 (m, 1H), 2.37 (m, 4H), 0.65-0.61 (m, 2H), 0.42-0.38 (m, 2H). MS: 523.6 (MH)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[CH:25]1([C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:4]3[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:13][CH2:14]2)=[O:29])[CH2:27][CH2:26]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)C2CC2)CC1
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of 1-(2-methoxy-5-nitrophenyl)-piperazine (500 mg, 2.1 mmol) in dichloromethane (50 ml) at 0° C. under argon was added triethylamine (0.59 ml, 4.2 mmol) and cyclopropane carbonyl chloride (2.1 mmol). Stirring was continued for 12 hrs. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous NaHCO3 and dichloromethane. The organic layer was dried over sodium sulphate and concentrated in vacuo to give the title compound (D17) in 90% yield. Found MH+ 306.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[C:13]3([CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12]2=[O:30])[CH2:7][CH2:6]1)=[O:4].[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:14]2[C:13]3([CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12](=[O:30])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:35]4[C:31](=[O:37])[CH2:32][CH2:33][C:34]4=[O:36])[CH2:10][CH2:9]3)[N:15]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C23CCCC3)cc1OC
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C23CCCC3)cc1OC

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-4-(3,4-dimethoxyphenyl)-2,3-diazaspiro[4.4]non-3-en-1-one (compound A10) and succinimide as starting compounds.
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:10]=[CH:11][C:12]([C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:18])[CH2:16][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)(c1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OC(Cn1ccnc1)(c1ccccc1)c1ccc(-c2ccccc2)cc1
Yield: 12.2 %

Procedure:
2.45 g (0.045 mol) of sodium methylate are dissolved in 20 ml of methanol, and 5.25 g (0.077 mol) of imidazole are added. A solution of 11.1 g (0.077 mol) of 1-(4-biphenylyl)-2-chloro-1-phenyl-ethanol in 50 ml of dimethylformamide is added dropwise to this mixture and the reaction mixture is heated under reflux for 16 hours. Thereafter, it is poured onto water and the crystals which form are extracted with hot acetonitrile. 3.2 g (21% of theory) of 1-(4-biphenylyl)-2-(imidazol-1-yl)-1-phenyl-ethanol of melting point 224° C. are obtained.