Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]1([O:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:25](=[O:26])[O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 4-methoxybenzenemethanamine (72.7 g) and triethylamine (83.6 ml) in CH2Cl2 (750 ml) was cooled on an ice-bath. Phenylchloroformate (91.4 g) was added dropwise and the reaction mixture was stirred at RT. The reaction mixture was washed three times with water and the precipitate was filtered off. The organic layer was separated, washed three times with a 5% aqueous NaHCO3 solution, dried (MgSO4), filtered and the solvent was evaporated. The precipitate was stirred in boiling diethyl ether (300 ml), filtered off and dried, yielding 84.4 g (65.5%) of phenyl [(4-methoxyphenyl)methyl]carbamate (interm. 2).
Reaction SMILES: [C:1]1([C:7]2[C:22](=[O:23])[NH:21][C:10]3=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[N:13][CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:31][C:32]1[N:33]([CH3:37])[N:34]=[CH:35][N:36]=1.O>CN(C=O)C>[C:1]1([C:7]2[C:22]([O:23][CH2:31][C:32]3[N:33]([CH3:37])[N:34]=[CH:35][N:36]=3)=[N:21][C:10]3=[C:11]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:12]=[N:13][CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2c(-c3ccccc3)nncc2cc1-c1ccccc1
Reactant: Cn1ncnc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nc2c(-c3ccccc3)nncc2cc1-c1ccccc1

Procedure:
3,8-Diphenyl-1H-pyrido[2,3-d]pyridazin-2-one (40 mg), cesium carbonate (174 mg) and 3-(chloromethyl)-2-methyl-2H-[1,2,4]triazole (prepared using the conditions described in EP-A-0170073) (27 mg) were stirred together at room temperature in DMF (4 ml) under nitrogen overnight. Water (25 ml) was added and the resultant solution was washed with dichloromethane (3×25 ml). The combined organic washings were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel, eluting with 5% methanol in dichloromethane. The product was recrystallised froim diethyl ether/ethanol/ethyl acetate, yielding 3,8-diphenyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrido[2,3-d]pyridazine as a white solid (8 mg). Data for the title compound: m.p. 222-223° C. 1H NMR (400 MHz, CDCl3) δ3.62 (3H, s), 5.67 (2H, s), 7.48 (3H, m), 7.56 (3H, m), 7.63 (2H, m), 7.85 (1H, s), 8.13 (2H, m), 8.20 (1H, s), 9.49 (1H, s); MS (ES+) m/e 395 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][CH2:31][C@:3]1([CH3:34])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C@H:16]([O:25][CH3:26])[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:33][CH2:32][CH2:31][C@:3]1([CH3:34])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C@H:16]([O:25][CH3:26])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Yield: 109.4 %

Procedure:
According to the general procedure B, from #195 (11.1 g, 21.6 mmol, 1 eq.), dichloromethane (100 mL) and trifluoroacetic acid (40 mL) was synthesized the crude desired material, to obtain #196 (10.1 g, quantitative yield) which was used in the next step without further purification. LC-MS (Protocol Z): m/z 428.5 [M+H+], retention time=0.9 minutes.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.Cl.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH:28]3[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:25])[CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: CCOC(=O)C1Cc2ccccc2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
150 mg (0.44 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]pyrimidine-4-carboxylic acid, 110 mg (0.48 mmol) ethyl 2,3-dihydro-1H-indole-2-carboxylate hydrochloride, 150.0 mg (0.47 mmol) TBTU and 150 μL (1.1 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was filtered through a syringe filter and the solution was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:11][CH:10]=1)C.[NH3:28]>CO>[C:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH2:28])=[CH:10][CH:11]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: N
Reactant: CCOC(=O)CCCNc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(NCCCC(N)=O)cc1
Temperature: 45 °C
Reaction time: 25 h
Yield: 56 %

Procedure:
4-[4-(4-tert-Butoxycarbonylaminobutyl)phenylamino]butyric acid ethyl ester 420 (0.44 g, 1.16 mmol) was added to 7N NH3 in methanol (40 mL). The reaction was stirred at 30° C. for 18 hours, at 45° C. for 25 hours, and finally at 50° C. for 84 hours. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20:1:0.1, chloroform/methanol/concentrated ammonium hydroxide, v/v) to provide 430 (0.23 g, 56%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 1.55 (m, 4H), 1.96 (m 2H), 2.37 (t, 2H), 2.50 (t, 2H), 3.11 (m, 4H), 6.52 (d, 2H), 6.97 (d, 2H). m/z (ESI) 350.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][NH2:15])[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]2[CH:34]=[C:33]([C:35](O)=[O:36])[NH:32][C:29]2=[CH:30][N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][NH:15][C:35]([C:33]3[NH:32][C:29]4=[CH:30][N:31]=[C:26]([Cl:25])[CH:27]=[C:28]4[CH:34]=3)=[O:36])[O:10][CH2:11][CH2:12][O:13]2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: COc1ccc(C2(CN)OCCO2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2(CNC(=O)c3cc4cc(Cl)ncc4[nH]3)OCCO2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of [2-(4-methoxyphenyl)-[1,3]-dioxolan-2-yl]methylamine (Preparation 45, 0.117 g, 0.56 mmol) in dichloromethane (5 mL) was added DIPEA (213 μL, 1.22 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 0.100 g, 0.51 mmol) and HOBT (0.076 g, 0.56 mmol). The resulting solution was stirred for 2 min then EDCI (0.117 g, 0.61 mmol) was added and stirring was continued for 18 h at rt. The reaction mixture was partitioned between dichloromethane (30 mL) and water (20 mL) and the layers separated. The aqueous phase was extracted with dichloromethane (3×20 mL) then the combined organics were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Recrystallisation from methanol/dichloromethane gave the title compound as an orange solid. δH (CDCl3): 3.81 (3H, s), 3.84-3.91 (4H, m), 4.05 (2H, m), 6.56 (1H, t), 6.76 (1H, s), 6.89 (2H, d), 7.44 (2H, d), 7.57 (1H, s), 8.68 (1H, s), 9.94 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(Nc2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottom flask is charged with 3-nitrophenylboronic acid (4.2 g, 25 mmol), dry molecular sieves (5 g), copper acetate (1.95 g, 12.5 mmol) and dry dichloromethane (150 mL). Triethylamine (8.7 mL, 62.5 mmol) is added followed by the addition of 4-fluoro-3-nitroaniline (2.27 g, 12.5 mmol). The resulting mixture is stirred at ambient temperature for three days. The mixture is filtered through celite and washed with EtOAc. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane=1:3) to give the desired product: 1H NMR (400 MHz, DMSO) δ 9.12 (s, 1 H), 7.82 (m, 1 H), 7.79-7.37 (m, 1 H), 7.73-7.70 (m, 1 H), 7.56-7.49 (m, 4 H); LC-MS: 278.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27]3)=[CH:22][CH:21]=2)[NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.CN(C=O)C>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)=[N:9][C:8]=2[C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[N:27]3)=[CH:22][CH:21]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC1CCC(C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)CC1
Temperature: 55 °C

Procedure:
A round bottom flask, charged with carbonyldiimidazole (252.2 mg, 1.55 mmol) and 4-methoxy-cyclohexanecarboxylic acid (mixture of cis/trans isomers) (242.9 mg, 1.54 mmol) was evacuated and filled with nitrogen. THF (15 mL) was added and the reaction mixture was stirred at 60° C. for 16 h. (3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methylamine hydrochloride salt (500 mg, 1.10 mmol) was then added and stirring was continued at 60° C. for another 20 h. After cooled to rt, the reaction mixture was diluted with 20 mL of EtOAc and washed with sat. NaHCO3 (3×30 mL) followed by brine (3×30 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (60% EtOAc in hexane→100% EtOAc). N-[(3-Chloropyrazin-2-yl)(2-phenyl-quinolin-7-yl)-methyl]-4-methoxycyclohexanecarboxamide was obtained as a yellow solid. To a solution of N-[(3-chloropyrazin-2-yl)(2-phenyl-quinolin-7-yl)-methyl]-4-methoxycyclohexanecarboxamide (440 mg, 0.91 mmol) in acetonitrile (20 mL) was added POCl3 (0.17 mL, 1.69 mmol) and DMF (0.3 mL). This mixture was heated to 55° C. under N2 for 2 h, concentrated under reduced pressure, and quenched with 2N NH3 in 2-propanol to pH 9. 2-Propanol was removed under reduced pressure and the residue was dissolved in dichloromethane (50 mL) and water (30 mL). Layers were separated and the organic phase was washed with brine and dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (2%→6% CH3CN in dichloromethane) to afford the individual cis-isomer and trans-isomers:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[C:33]([OH:35])=[O:34])[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1.[C:37]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[C:33]([O:35][CH3:37])=[O:34])[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnccc1CC(=O)N1CCC([C@H]2c3ncc(Br)cc3CCc3cc(Cl)cc(Br)c32)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnccc1CC(=O)N1CCC([C@H]2c3ncc(Br)cc3CCc3cc(Cl)cc(Br)c32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the product of Example 2 (1.0 mmol) dissolved in anhydrous DMF add solid K2CO3 (1.2 mmol, anhydrous) and CH3I (1.2 mmol). After stirring the reaction mixture at room temperature for 24 hours, concentrate the mixture in vacuo, dilute with CH2Cl2 and wash with water. Dry the organic phase over anhydrous MgSO4, filter and concentrate in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1cccnc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccnc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(3-pyridyl)acetate (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp=146-157° C.). The reaction was monitored by tlc (Rf=0.1 in CHCl3/MeOH 98:2) and the product was purified by silica gel chromatography using 959:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1cc(O)cc(F)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1cc(F)cc(OC)c1
Reaction time: 8 h
Yield: 15.9 %

Procedure:
To a stirred mixture of methyl 5-fluoro-3-hydroxyphenylacetate (3.3 g, 15.7 mmol) and potassium carbonate (1.82 g, 50 mmol) in DMF (30 ml) was added methyl iodide (1.82 g, 50 mmol) at room temperature and the reaction mixture was stirred overnight. Then the mixture was diluted with water (50 ml) and extracted with ether. The combined extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 150 g; hexane/ethyl acetate (10/1)) afforded 495 mg (55%) of methyl 5-fluoro-3-methoxyphenylacetate as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:20]1C(O)=CC=CC=1C.[OH-].[K+].CC(O)=O>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: CS(=O)(=O)c1ccc(N=Nc2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(O)ccc1N=Nc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
For these studies, half of the diazonium salt from example 1 was added to a solution of m-cresol (0.285 g, 2.34 mmol) and KOH (0.13 g, 2 mmol) in THF. The resulting red mixture was stirred for 0.5 h and then neutralized with HOAc to give a orange solid. This solid was filtered and recrystallized from THF/Hexanes to give 0.35 g (58%) of Compound 2.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)(=[O:17])=[O:16])[N:12]([C:25]2[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CC(O)C>[ClH:39].[F:31][C:26]1[C:25]([N:12]2[C:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)(=[O:17])=[O:16])=[CH:14][C:10]([CH2:9][NH:7][CH3:6])=[N:11]2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Cc1cccc(S(=O)(=O)c2cc(CN(C)C(=O)OC(C)(C)C)nn2-c2cccnc2F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(S(=O)(=O)c2cccc(C)c2)n(-c2cccnc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
tert-Butyl({1-(2-fluoropyridin-3-yl)-5-[(3-methylphenyl)sulfonyl]-1H-pyrazol-3-yl}methyl)methylcarbamate (302 mg) was dissolved in ethyl acetate (2 mL) and 2-propanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 216 mg, yield 83%). melting point 202-205° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16])([O-])=O.C(O)CC.N.[H][H]>[Pd].O>[CH3:16][O:15][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:9][C:4]=1[NH2:1]
Reactant: CCC(=O)Nc1ccc(OC)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CCCO
Product: CCC(=O)Nc1ccc(OC)c(N)c1
Reaction time: 1 h

Procedure:
114 parts of 2-nitro-4-propionamidoanisole, 160 parts of propanol, 3.4 parts of a 30% aqueous solution of ammonia and 2 parts of a 50% suspension of palladium on activated charcoal, moist with water, in 3 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 25 bar and a temperature of 120° C., hydrogenation is carried out for 1 hour. 2-Methoxy-5-propionamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1I)=[O:4].[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:19][N:18]([CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1I
Reactant: CN(N)c1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NN(C)c1ccccn1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.28 mmol), N,N-diethylenediamine (9 μL, 0.086 mmol), N-methyl-N-pyridin-2-yl-hydrazine (0.105 g, 0.86 mmol), CuI (0.01 g, 0.057 mmol), 4 Å ms (0.114 mg) and K2CO3 (0.118 g, 0.861 mmol) in DMF (3 mL) was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate, washed twice with 5% LiCl, concentrated and the crude material was purified by silica gel chromatography (0-20% EtOH in DCM) to give 5-(3,3-dimethyl-but-1-ynyl)-3-(N′-methyl-N′-pyridin-2-yl-hydrazino)-thiophene-2-carboxylic acid methyl ester in 50% yield. This was then dissolved in pyridine (5 mL) and treated with neat trans-4-methyl-cyclohexanecarbonyl chloride (0.132 g, 0.825 mmol). The reaction was heated for 16 h at 85° C. and quenched with saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude material was then dissolved in a 3:2:1 mixture of THF:MeOH:water (5 mL), treated with lithium hydroxide monohydrate (0.69 g, 1.65 mmol) and heated to 60° C. for 1 hour. The organic volatiles were evaporated under reduced pressure and the crude material was purified by HPLC to afford the title compound. MS (m/z): 454.1 [M+H]−; HPLC retention time: 3.95 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19].[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[K+].ClOC(C)(C)C.[C:34]1([C:40]#[CH:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH+:9]1[CH:41]=[C:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:11]([C:12]2[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=2[F:18])[NH:10]1
Reactant: Fc1cccc(F)c1N=NNc1c(F)cccc1F
Reactant: C#Cc1ccccc1
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Product: Fc1cccc(F)c1N1N[NH+](c2c(F)cccc2F)C=C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of triazene 8d (808 mg, 3 mmol) and anhydrous potassium hexafluorophosphate (750 mg, 4 mmol) in dry dichloromethafne (20 mL) in the dark at −78° C. is added tert-butyl hypochlorite (500 μL, 4.4 mmol), upon which the mixture instantly darkens. Stirring is pursued at −78° C. for 30 min, and phenylacetylene 9a (660 μL, 6 mmol) is added. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether afford, after drying under vacuum, triazolium salt 10da as an off-white solid (0.79 g, 51%). Analytical samples were obtained after recrystallization by vapor diffusion of diethyl ether in an chloroform solution of 10da. 1H-NMR (CD3CN, 300 MHz): δ=9.23 (s, 1H), 7.94-7.83 (m, 2H), 7.70-7.66 (m, 1H), 7.63-7.53 (m, 4H), 7.47 (t, J=7.9 Hz, 2H), 7.37 (td, J=8.0, 3.3 Hz, 2H). 13C-NMR (CD3CN, 75 MHz): δ=157.7 (d, J=258 Hz), 157.0 (d, J=257 Hz), 147.3, 137.6 (t, J=10 Hz), 136.9 (t, J=10 Hz), 133.9, 133.1, 130.9, 130.0, 122.1, 114.9 (d, J=21 Hz), 114.7 (d, J=22 Hz), 113.7 (t, J=8 Hz), 111.9 (t, J=8 Hz). 19F-NMR (CD3CN, 282 MHz): δ=−72.0 (d, J=705 Hz, 6F), −117.4 (2F), −119.2 (2F). HR-MS (ESI): Calcd. for C20H12F4N3 [M+]: 370.0962. found 370.0967.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][O-].[Na+].C[O:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17].[NH4+].[Cl-]>C1(C)C=CC=CC=1.CO.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:14](=[O:13])[CH2:15][CH:16]([O:18][CH3:19])[O:17][CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CO/C=C/C(=O)OC
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(CC(=O)Nc1cccc(F)c1)OC
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
3-Fluoroaniline (50 g, 450 mmol) was dissolved in toluene (500 ml) and 25% NaOMe in MeOH (120 ml) and methyl (2E)-3-(methyloxy)-2-propenoate (57.4 ml, 495 mmol) were added. The mixture was then heated to 70° C. and stirred at this temperature for 2.5 hours. The solvent was then reduced to around a quarter of the original volume and the reaction was then treated with NH4Cl until pH 7 was reached (approx 500 ml used). EtOAc was added to the reaction and the layers separated, the aqueous layer was then extracted three times with EtOAc and the combined organic layers dried with MgSO4. The solvents were removed and the crude residues were purified by column chromatography on silica gel using a 30-50% EtOAc/40-60 petroleum ether gradient. Fractions containing product were concentrated to afford the desired compound (40.68 g, 40%) and a less pure batch (6.17 g, 6%)