Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH:15]([C:16]([O:18]C)=[O:17])[CH2:14][CH:13]=[CH:12][CH2:11]2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH:13]=[CH:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC=CCC1CSc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: O=C(O)C1CC=CCC1CSc1ccc(F)cc1
Reaction time: 19 h

Procedure:
A solution of methyl(1R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]methyl}cyclohex-3-ene-1-carboxylate (656 mg, 2.34 mmol) in methanol (1.0 ml) and ethylene glycol dimethyl ether (5.0 ml) was treated with a 2 M aqueous solution of lithium hydroxide (6.0 ml). After stirring for 19 h, the reaction mixture was adjusted to pH 2 with a 2 M aqueous solution of hydrochloric acid and partitioned between water and ethyl acetate. After separating the organic phase, the aqueous phase was extracted with an additional portion of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Removal of the solvent on a rotary evaporator provided (1R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]methyl}cyclohex-3-ene-1-carboxylic acid as a golden-yellow syrup.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A mixture of (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and 50 mL THF was cooled in an ice bath. To this was added benzyl chloroformate (0.77 mL, 5.5 mmol), followed by triethylamine (1.39 mL, 10 mmol). After removing the ice bath, the reaction was stirred for 4 h. The mixture was poured into ice water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using EtOAc in hexanes (0-40%) gave benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.29 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.87 (s, 1H), 3.52-2.95 (m, 6H), 2.41-2.35 (m, 1H), 2.10-1.79 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28]Br>O.C(Cl)Cl.CCO>[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCc1ccc2ccccc2c1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc2ccccc2c1Br)C(=O)OCC
Yield: 95.6 %

Procedure:
To a solution of NaOEt prepared from 9.66 g of sodium and 210 mL of dry EtOH was added 63.76 mL of diethyl malonate and the reaction mixture refluxed for 2 h. To the resulting yellow solution was added in small portions 126 g of 1-bromo-2-bromomethylnaphthalene and the reaction mixture refluxed for 16 h. Distillation of ethanol from an oil bath (100°-110° C.) through a simple Claisen head gave a yellow suspension, to which was added 350 mL of CH2Cl2 and 350 mL of H2O. The aqueous layer was extracted twice with 120-mL portions of CH2Cl2, and the combined organic layer was washed three times with 100-mL portion of H2O, dried (MgSO4) and evaporated to give 152 g (95.6%) of the ester as a yellow solid, mp 60°-65° C. Recrystallization from acetic acid gave 137 g (86.2%) of the pure diester as a colorless solid, mp 77°-79° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([OH:11])([CH3:10])[C:8]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:26][CH2:27][CH2:28]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C.CCOCC>[ClH:18].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[CH:26][CH2:27][CH2:28][N:14]2[CH2:13][CH2:12][C:8]3([O:7][C:6](=[O:17])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9]3([OH:11])[CH3:10])[CH2:16][CH2:15]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(C(=CCCBr)c2ccc(Cl)cc2)cc1
Reactant: CCCCN1C(=O)OC2(CCNCC2)C1(C)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)CC(C)C
Product: CCCCN1C(=O)OC2(CCN(CCC=C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)C1(C)O
Product: Cl
Reaction time: 6 h
Yield: 79.3 %

Procedure:
A mixture containing 7.27 g of 3-butyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 12.89 g of 4,4-bis(4-chlorophenyl)-3-butenyl bromide, 4.98 g of anhydrous potassium carbonate and 0.6 g of potassium iodide in 73 ml of methyl isobutyl ketone is gently refluxed under argon while stirring for 6 hours. After cooling down, the inorganic salts are filtered off, washed with methyl isobutyl ketone, the filtrate is washed with water to neutral, dried over anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure. After recrystallizing the evaporation residue from ethanol, the product obtained is dissolved in ether and the hydrochloride is precipitated by adding ethereal hydrogen chloride solution to obtain 79.3% of the title hydrochloride, m.p.: 230°-233° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22]C=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CC[N:35](C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH2:17][C:18]3[CH:19]=[CH:20][N:35]=[CH:22][CH:23]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)NCc4ccccc4)C3)nc(N)n2)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)NCc3ccncc3)C2)n1
Temperature: 150 °C
Yield: 47.1 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(phenylmethyl)-3-piperidinecarboxamide (190 mg, 0.440 mmol), 3 mL of EtOH, Hunig's base (0.31 mL, 1.76 mmol), and hydrazine anhydrous (0.083 mL, 2.64 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The yellow residue was sonicated in EtOAc at 50° C., and the solid was filtered. This material was then sonicated in water at 50° C., and the solid was filtered and washed with water to afford the title compound (92 mg) as a light yellow solid. LC-MS (ES) m/z=444 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.37-1.55 (m, 1H), 1.62-1.80 (m, 2H), 1.96 (m, 1H), 2.35-2.45 (m, 1H), 2.81-3.05 (m, 2H), 4.18-4.46 (m, 3H), 4.56 (m, 1H), 5.38 (s, 2H), 6.10 (s, 2H), 6.65 (s, 1H), 7.25 (d, J=5.8 Hz, 2H), 7.59 (dd, J=8.6, 1.3 Hz, 1H), 7.67-7.78 (m, 1H), 7.96 (s, 1H), 8.45-8.65 (m, 3H), 11.51 (s, 1H).
Reaction SMILES: C(O[CH:4]([O:8][CH2:9][CH3:10])OCC)C.[C:11]([C@@H:16]([C@H:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[OH:19])[OH:17])([O:13][CH2:14][CH3:15])=[O:12].[C:25]1([CH3:35])[CH:30]=CC(S(O)(=O)=O)=[CH:27][CH:26]=1>CN(C)C=O>[CH3:4][O:8][C:9]1[CH:10]=[CH:30][C:25]([CH:35]2[O:19][C@@H:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@H:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:17]2)=[CH:26][CH:27]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1OC(c2ccc(OC)cc2)O[C@H]1C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of triethylorthoformate (108 g, 0.74 mol) anisic aldehyde (89.4 g, 0.66 mol), diethyl L-tartrate (153.1 g, 0.743 mol), dimethylformamide (294 g) and p-toluenesulfonic acid (1.3 g) was heated at 100°-105° C. for 4 h. During the next 5 h, low boiling materials (100 mL) were removed by distillation (maximum pot temperature: 100° C., 300-360 mm vacuum). Sodium acetate (0.62 g) was added. Most of the dimethylformamide was then removed under reduced pressure (10 mm, maximum pot temperature 110° C.). The residue was cooled (25° C.) and diluted with toluene (500 mL). The mixture was washed with aqueous sodium bicarbonate (100 mL) and with brine (3×200 mL). Removal of solvents gave 211 g of crude product. Chromatography of a portion of the crude product followed by Kugelrohr distillation (0.5 mm, bath temperature 240°-250° C.) gave a sample of (4R,5R)-2-(4-methoxyphenyl)-4,5-dicarboethoxy-1,3-dioxolane, GLC purity: 98.6% [α]D25 -31.6° (c,1.14,ethanol). 1H-NMR (CDCl3)δ7.52 (2H,d,J=7.5 Hz), 6.91 (2H,d,J=7.5 Hz), 6.11 (1H,s), 4.92 (1H,d,J=4.0 Hz), 4.81 (1H,d,J=4.0 Hz), 4.37-4.25 (4H, 2 q, overlapping, J=7.2 Hz), 3.81 (3H,s), 1.38-1.29 (6H, 2 t, overlapping, J=7.2 Hz). IR (KBr) 2980, 1750, 1610, 1590, 1510 cm.-1MS m/e (% abundance) 324 (2), 251(12, 152(92), 135(100), 121(40), 108(16), 91(5), 77(14), 51(5).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([NH:27][C:28]1[CH2:32][S:31][C:30](=[O:33])[N:29]=1)[C:25]#[CH:26].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:24][C:25]#[CH:26])=[N:29][C:30](=[O:33])[S:31]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a suspension of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (35.0 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (23.9 g) in 2-propanol (400 mL) was added piperidinium acetate (15.0 g) at room temperature. The reaction mixture was stirred at 80° C. for 4 hr and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was removed by filtration. Water and ethyl acetate were added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give a solid. The obtained solid was recrystallized from ethyl acetate/heptane/diisopropyl ether to give the title compound (28.9 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:17][CH:16]=3)[C:11]2=[O:29])=[CH:6][CH:5]=1)([O-])=O.O.NN>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])=[CH:19][CH:20]=3)[C:11]2=[O:29])=[CH:8][CH:9]=1
Reactant: O=c1n(-c2ccc(OCC(F)(F)C(F)F)cc2)ccn1-c1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2ccn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Reaction time: 14 h
Yield: 95.2 %

Procedure:
Ferric chloride (0.2 g) and activated carbon (2.0 g) were added to a solution of 1-(4-nitrophenyl)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (20.5 g) in methanol-tetrahydrofran (75 ml:75 ml), to which hydrazine hydrate (8.0 ml) was added dropwise over the period of 10 minutes. After the mixture was refluxed with stirring for 14 hours, ferric chloride (0.2 g), activated carbon (2.0 g) and hydrazine hydrate (8.0 ml) were added thereto and the reaction mixture was refluxed with stirring for further 6 hours. The activated carbon was filtered off and washed with methanol (100 ml). The filtrate and the washing were combined and distilled off under reduced pressure. The residue thus obtained was dissolved in ethyl acetate (700 ml). The ethyl acetate layer was washed with water (200 ml×4), dried over anhydrous magnesium sulfate and distilled off under reduced pressure to give 1-(4-aminophenyl)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (18.1 g, 95%) as a pale yellow powder.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:28][CH2:29][O:30]C)[CH:4]=[CH:5]2.[C:32](O)(=O)C>O>[C:29]([O:28][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH:11]=[CH:10][C@@H:9]35)(=[O:30])[CH3:32]
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OCC4CCCCO4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](OCC4CCCCO4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-ene (2.17 g, 5.08 mmol) is dissolved in water (65 ml) and glacial acetic acid (65 ml) and then stirred for 6 hours at 100° C. The volatile components are eliminated using the Rotavapor. The residue thus obtained is purified by flash chromatography (130 g of silica gel; mobile phase: methylene chloride/methanol=9:1). The product is dissolved in a mixture of water and glacial acetic acid and lyophilised. Yield: 1.55 g 4,5α-epoxy-17-methyl-6α-((2-tetrahydropyranyl)-methoxy)-morphinan-7-en-3-ol acetate (68.8%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3([CH3:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.Cl[C:23]1[C:24]2[C:31]([CH3:32])=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>CS(C)=O>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3([CH3:21])[CH2:20][CH2:19][N:18]([C:23]4[C:24]5[C:31]([CH3:32])=[CH:30][NH:29][C:25]=5[N:26]=[CH:27][N:28]=4)[CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: CC1(C(=O)Nc2cccc(-c3nnn[nH]3)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(-c5nnn[nH]5)c4)CC3)c12
Temperature: 105 °C
Yield: 4.3 %

Procedure:
N-(3-(1H-tetrazol-5-yl)phenyl)-4-methylpiperidine-4-carboxamide from step B (93 mg, 0.29 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (49 mg, 0.29 mmol), N,N-diisopropylethylamine (0.19 g. 1.45 mmol), isopropanol (4.0 mL), and DMSO (0.5 mL) were combined in a pressure rated sealed tube and heated at 105° C. for 18 hours. The mixture was concentrated, and the residue was purified by preprative HPLC to give the title compound in 4.3% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:23]([NH:27][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:10])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN
Reactant: O=C(O)c1cccc(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)c1cccc(Cl)n1
Reaction time: 16 h
Yield: 47.6 %

Procedure:
6-Chloro-pyridine-2-carboxylic acid (500 mg, 3.17 mmol), EDC.HCl (1.34 g, 6.98 mmol) and HOBN (1.42 g, 7.93 mmol) were dissolved in DCM (30 mL) and NEM (914 mg, 7.93 mmol) and n-butylamine (376 μL, 3.81 mmol) were added. The reaction mixture was stirred for 16 h, washed with sat aq NaHCO3 (2×20 mL), 1 M aq HCl (2×20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (321 mg, 48%) as a colourless liquid. LCMS (ES+): 213.5 [MH]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:3].[CH3:21][S:22]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([Cl:32])=[O:31])=[CH:28][CH:27]=1)(=[O:24])=[O:23]>>[ClH:32].[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]([C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([CH3:1])[CH3:3])[C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][CH:28]=1)[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CCNc1c(C(C)C)cccc1C(C)C
Product: CCN(CC)CCN(C(=O)c1ccc(NS(C)(=O)=O)cc1)c1c(C(C)C)cccc1C(C)C
Product: Cl

Procedure:
In a manner similar to Example I react N-[2,6-bis(1-methylethyl)phenyl]-N',N'-diethyl-1,2-ethanediamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtain the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39](Cl)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.O>CN(C)C=O>[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CNC(=O)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 70 °C
Yield: 35.8 %

Procedure:
1.58 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.38 g of N-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)glycine ethyl ester were dissolved in 15 ml of N,N-dimethylformamide; 1.68 ml of N-ethyldiisopropylamine was added, followed by stirring under heating at an external temperature of 70° C. for 5 hours. After cooling, water was added; the reaction mixture was extracted with tetrahydrofuran. After concentration under reduced pressure, the precipitated crystal was twice recrystallized from ethanol-tetrahydrofuran (1:1), collected by filtration, and dried, to yield 995 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:12])[C:10]2[CH:9]=[C:8]([O:11][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][O:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1(C)OCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC1(C)OCc2ccc(Oc3ccc([N+](=O)[O-])cc3)cc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
3,3-Dimethyl-1,3-dihydro-2-benzofuran-5-ol (Intermediate 18, 500 mg, 3.04 mmol) and potassium carbonate (1.05 g, 7.6 mmol) were suspended in acetonitrile (7.5 mL). 1-Fluoro-4-nitrobenzene (386 mg, 2.74 mmol) was added and the mixture was stirred under nitrogen at 70° C. overnight and then for 4 hours at 80° C. Further 1-fluoro-4-nitrobenzene (86 mg, 0.6 mmol) was added and the mixture heated to reflux until achieving reaction completion. After cooling water and ethyl acetate were added and the two layers were separated. The organic phase was washed three times with brine, then it was dried over anhydrous Na2SO4 and concentrated to dryness. The residue was triturated in isopropanol and the solid washed with further isopropanol to give the title compound (500 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17][C:18]#[N:19])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C=O)C>C(O)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:16][CH2:17][C:18]3[NH:28][N:27]=[N:26][N:19]=3)[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(N(CCC#N)Cc3cccs3)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)c1ccc(-c2csc(N(CCc3nnn[nH]3)Cc3cccs3)n2)cc1

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-[2-(1H-tetrazol-5-yl)-ethyl]-thiophen-2-ylmethyl-amine was prepared following general procedure H using 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionitrile (278 mg, 0.756 mmol), sodium azide (657 mg, 99%, 10 mmol), ammonium chloride (535 mg, 10 mmol) and DMF (3 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:1, with 0.5% v/v acetic acid) gave the product compound (110 g, 0.268 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17].[CH2:23]([NH:26][C:27]#[N:28])[CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[N:28][C:15]([CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])=[N:14]1
Reactant: CCCNC#N
Reactant: CC(C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNc1nc(C(C)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 2 h
Yield: 700.8 %

Procedure:
7.8 g (0.02 mol) of 2-trifluoromethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.9 g (0.002 mol) of propyl cyanamide were dissolved in 50 ml of tetrahydrofuran, and 2.6 g (0.026 mol) of triethylamine was dropwise added thereto under stirring and cooling with ice. After completion of the dropwise addition, the stirring was continued at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, hexane was distilled off under reduced pressure. Further, the residue was subjected to distillation under reduced pressure. The fraction having a boiling point of 110°-120° C./0.1-0.2 mmHg was subjected to recrystallization from hexane to obtain 6.1 g (yield: 70%) of the desired compound having a melting point of from 73° to 74.5° C. as white prismatic crystals.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]#[N:29].O>CN(C)C=O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:27][C:28]#[N:29])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: N#CCBr
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 53.5 %

Procedure:
A suspension of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 52 mg, 0.20 mmol), potassium carbonate (43 mg, 0.31 mmol), bromoacetonitrile (15 μL, 0.22 mmol) in anhydrous N,N-dimethylformamide (1 mL) was stirred at 60° C. for 2.5 hours. After cooling to room temperature, water (10 mL) was added thereto and the precipitated solid was filtered off. The obtained solid was dried under reduced pressure to give the target compound (32 mg) as a pale brown solid (Yield 54%).