Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:26]3[CH:31]=[CH:30][C:29]([S:32][C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:39][C:36]1[CH:35]=[CH:34][C:33]([S:32][C:29]2[CH:30]=[CH:31][C:26]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([S:10][C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)=[CH:12][CH:13]=3)([C:18]([F:21])([F:19])[F:20])[C:22]([F:23])([F:24])[F:25])=[CH:27][CH:28]=2)=[CH:38][CH:37]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Sc2ccc(C(c3ccc(Sc4ccc([N+](=O)[O-])cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Sc2ccc(C(c3ccc(Sc4ccc(N)cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
Compound 8 was is prepared by hydrogenating 2,2-bis[4-(4-nitrophenylthio)phenyl]hexafluoropropane (Compound 7) in a Parr apparatus under 4 atmospheres of hydrogen over palladium-on-charcoal catalyst in ethyl alcohol solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:9])=[CH:4][CH:3]=1.C(OCC)(=O)C.CO.C(O)(=O)C.O>O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:23][C:22]1[C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:9])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
Under an atmosphere of nitrogen, 29 g (0.187 mole) of titanium trichloride was added portionwise (cautiously; in hood) to 200 g of ice and the resulting solution was diluted to 250 ml volume with water. This was added, all at once, at 30° C. to a stirred solution of 11.0 g (0.0312 mole) of (4-chlorophenyl)[2-[(3-nitro-2-pyridinyl)amino]phenyl]methanone, 300 ml of ethyl acetate: methanol (1:1), 100 ml of acetic acid: water (1:1) and 20 ml more solution of titanium trichloride. The reaction mixture was stirred for 20 min then diluted with one liter of water and filtered. The filter cake was washed with water and then partitioned between 200 ml of methylene chloride and 75 ml of 10% aqueous sodium hydroxide solution. The methylene chloride layer was washed with 75 ml of water, dried over sodium sulfate and concentrated in vacuo. The residue (7 g) was recrystallized from ethyl acetate-isopropyl ether to give 6.0 g of gold solid, m.p. 145°-146° C.
Reaction SMILES: [H-].[Na+].[C:3](=O)([O:7]CC)[O:4][CH2:5][CH3:6].[C:11]([C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])(=[O:13])[CH3:12].Cl>C(OCC)(=O)C.C(O)C.C(OCC)C>[CH2:5]([O:4][C:3]([CH2:12][C:11]([C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])=[O:13])=[O:7])[CH3:6]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C(C)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cc(CC(CC)C(=O)OCC)ccc1OC
Yield: 58.2 %

Procedure:
To anhydrous diethyl ether (20 mL), sodium hydride (60% oil dispersion, 1.27 g, 52.9 mmol) was added under stirring and cooling with ice. Successively, after diethyl carbonate (2.25 g, 19.0 mmol) was added, the mixture was stirred for 30 minutes at room temperature. Following this, a mixture of ethyl 3-(3-acetyl-4-methoxyphenyl)-2-ethylpropanoate (3.53 g, 12.7 mmol), anhydrous diethyl ether (10 mL) and absolute ethanol (0.24 mL) was added dropwise over 20 minutes, and then the mixture was refluxed for 6 hours. After cooling, the reaction mixture was added slowly to a mixed solution of 2 mol/L hydrochloric acid (45 mL) with ethyl acetate (80 mL) under stirring and cooling with ice. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=9:1 v/v) to afford 2.59 g (58%) of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:18]#[N:19])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:18]([C:11]1[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9][N:10]=1)#[N:19]
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: N#Cc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 45 h
Yield: 87 %

Procedure:
4-Phenylpyridine N-oxide (3.13 g, 18.3 mmol) was dissolved in nitroethane (30 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 45 hrs, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (2.87 g, 89%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[CH3:14])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:20]([O:19][C:17]([N:6]1[CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][C:13]([F:15])([F:16])[CH3:14])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: COC(=O)C1CC(CCCC(C)(F)F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)CCCC1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 4-(4,4-difluoro-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (88 mg, 0.21 mmol, 1 equiv) in THF (1.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (45 mg, 1.07 mmol, 5 equiv). The reaction mixture was stirred at rt overnight. The THF was removed under vacuum. The residue was diluted with water and washed with ether. The aqueous layer was taken up in ethyl acetate, partitioned with 10% citric acid. The organic layer was washed with water (1×), brine (1×), dried and concentrated to give 4-(4,4-difluoro-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (66 mg, 96%).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:27]=[CH:26][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:25][CH:23]([CH3:24])[CH2:22][CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:27][CH:26]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 24.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-isopentyl-1-piperidinecarboxamide formate (0.40 g, 1.05 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.427 g, 1.05 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.194 g, 0.26 mmol).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[C:9](=[O:17])[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22](=[O:23])[C:7]1=2)C.C([O:27]C(C1C(=O)C2C=C(NC(=O)C)C=CC(=O)C=2NC=1)=O)C.C(OC(=O)CN1C=C(C(OCC)=O)C(=O)C2C=C(Cl)C=CC(=O)C1=2)C>>[C:12]([C:10]1[C:9](=[O:17])[C:8]2[CH:18]=[C:19]([OH:27])[CH:20]=[CH:21][C:22](=[O:23])[C:7]=2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[CH:11]=1)([OH:14])=[O:13]
Reactant: CCOC(=O)Cn1cc(C(=O)OCC)c(=O)c2ccccc(=O)c21
Reactant: CCOC(=O)c1c[nH]c2c(=O)ccc(NC(C)=O)cc2c1=O
Agent: CCOC(=O)Cn1cc(C(=O)OCC)c(=O)c2cc(Cl)ccc(=O)c21
Product: O=C(O)Cn1cc(C(=O)O)c(=O)c2cc(O)ccc(=O)c21

Procedure:
In the same manner, but replacing 3-(ethoxycarbonyl)4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester with an equivalent amount of either 3-(ethoxycarbonyl)-4,9-dihydro-6-(N-methylacetylamino)-4,9-dihydro-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester, 6-(acetylamino)-4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid ethyl ester or 6-chloro-3-(ethoxycarbonyl)-4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester, gave the same product, namely 3-carboxy-4,9-dihydro-6-hydroxy-4,9-dioxo-1H-cyclohepta[b]pyridine-1-acetic acid (I; R1 =COOH and R2 =6-OH); mp>250° C. (after recrytallization from acetone); nmr (DMSO-d6) δ5.5 (s, 2H), 7.5 (d, H), 8.3 (d, 1H),8.9 (s, 1H); ir (Nujol*) 2900, 1743, 1694 cm-1 ; uv λ max (MeOH) 341 nm (ε12,500), 237 (32,000); Anal Calcd for C13H9NO7 : C, 53.62% H, 3.12% N, 4.81%; Found: C, 53.22% H, 3.05% N, 4.73%.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:8]=[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([F:13])[CH:12]=1.[C:23](=[O:25])=[O:24]>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([F:13])[C:12]=1[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: Fc1ccc(COc2cc(F)cc(F)c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 59 %

Procedure:
BuLi (1.6 M in hexane, 27.1 mL, 43.4 mmol) was added to a solution of 3,5-difluoro-(4-fluoro-benzyloxy)-benzene (10.5 g, 41.4 mmol) in dry THF at −78° C., under Argon, and the reaction mixture maintained at this temperature for 1 h whereupon carbon dioxide gas was bubbled into the solution over a 10 min period. The reaction mixture was then warmed up to room temperature and water added. The resulting mixture was extracted with diethyl ether. The aqueous phase was adjusted to pH 2 with HCl and extracted with ethyl acetate. The combined ethyl acetate layers were washed with HCl (0.1 N), then dried over sodium sulfate, filtered and evaporated to leave a white solid. This was triturated with pentane-diethyl ether to afford the title compound (6.8 g, 59%) as a white solid. MS: m/e=280.9 (M−H−).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:25][C:26]1[CH:27]=[C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:41][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]3)[O:35][N:34]=2)[CH:29]=[CH:30][C:31]=1[CH3:32]>ClCCl.N1C=CC=CC=1>[CH3:32][C:31]1[CH:30]=[CH:29][C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:39][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:41]3)[O:35][N:34]=2)=[CH:27][C:26]=1[NH:25][C:11]([C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][CH:9]=1)=[O:13]
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: Cc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(C)ccn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (24i) (100 mg, 0.568 mmol) in anhydrous dichloromethane (5 mL) at 0° C. under Argon was added dropwise oxalyl chloride (53 uL, 0.624 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated. A stirring mixture of the acid chloride and methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (82 mg, 0.283 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 2 hour. The solvent was concentrated and the crude product was purified by silica chromatography to give methyl 3-(3-(4-methyl-3-(7-methylimidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F61). 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 9.33 (d, J=7.2 Hz, 1H), 8.52 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 7.6 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.03 (dd, J=1.6, 7.2 Hz, 1H), 4.39-4.33 (m, 2H), 4.31-4.24 (m, 1H), 4.22-4.16 (m, 2H), 3.59 (s, 3H), 2.43 (s, 3H), 2.36 (s, 3H). MS m/z 447.17 (M+1)+.
Reaction SMILES: C[O:2][C:3](=O)[NH2:4].[Cl:6][C:7]1[C:8]([F:16])=[C:9]([CH2:13][CH2:14]N)[CH:10]=[CH:11][CH:12]=1>O>[Cl:6][C:7]1[C:8]([F:16])=[C:9]2[C:10](=[CH:11][CH:12]=1)[C:3](=[O:2])[NH:4][CH2:14][CH2:13]2
Reactant: NCCc1cccc(Cl)c1F
Reactant: COC(N)=O
Solvent: O
Product: O=C1NCCc2c1ccc(Cl)c2F
Temperature: 150 °C
Yield: 3.9 %

Procedure:
[2-(3-Chloro-2-fluoro-phenyl)-ethylamine]-carbamic methyl ester (890 mg, 3.85 mmol) and polyphosphoric acid (15 mL) were added to a 1-L, round bottom flask equipped with a magnetic stirring bar and reflux condenser. The reaction mixture was heated in an oil bath at 140-160° C. for 2 hours while keeping vigorous stirring. The reaction mixture was then allowed to cool to room temperature and poured into H2O (100 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. MgSO4, filtered and concentrated to give a yellowish oil which was crystallized from Et2O to give title compound as a white solid (30 mg, 4%). MS: 200.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:9])[CH2:4][C:5](=O)[CH2:6][CH3:7].[NH3:10]>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:9])[CH:4]=[C:5]([NH2:10])[CH2:6][CH3:7]
Reactant: CCC(=O)CC(=O)NC
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCC(N)=CC(=O)NC
Temperature: 25 °C

Procedure:
A solution of N-methyl propionylacetamide (4.25 g, 32.9 mmol) in 30 ml xylene was bubbled with ammonia gas at 110° C. for 2 hrs. After cooling to room temperature, the mixture was diluted with 30 ml of CHCl3 and dried (Na2SO4). After evaporation of solvent, N-methyl 3-amino-2-pentenamide was obtained as light-gray oil (4.15 g, 98).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[OH-].[Na+]>C(O)C>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[N:1]=[C:2]3[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]3=[CH:4][C:14]=2[CH2:13]1
Reactant: Nc1ccc(C=O)c(N)c1
Reactant: CN1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2nc3cc(N)ccc3cc2C1
Yield: 42.5 %

Procedure:
A solution of 2,4-diaminobenzaldehyde (1.00 g, 7.34 mmol), 1-methyl-4-piperidinone (1.08 ml, 8.81 mmol) and 4N aqueous sodium hydroxide solution (11 ml) in ethanol (70 ml) was stirred at 60° C. for 16 hrs, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The obtained crude product was purified by NH-silica gel chromatography (elute solvent; ethyl acetate) and treated with ethyl acetate-isopropyl ether (1:5) to give the title compound (666 mg) as a powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]1([S:15]([N:18]2[C:26]3[CH:25]=[C:24]([Sn:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=[C:22]([NH2:31])[C:21]=3[CH:20]=[N:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1>[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[C:22]([NH:31][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[O:7])[CH:23]=[C:24]([Sn:27]([CH3:29])([CH3:28])[CH3:30])[CH:25]=3)[CH:20]=[N:19]2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccco1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: Cl
Solvent: c1ccncc1
Product: C[Sn](C)(C)c1cc(NC(=O)c2ccco2)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reaction time: 1 h

Procedure:
2-Furancarbonyl chloride (0.199 ml) was added to a stirred solution of 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (580 mg) in pyridine (10 ml) at RT. The mixture was stirred for 1 h. After this time, the mixture was acidified with 5 N HCl and extracted into ether (2×40 ml). The combined extracts were washed with aq sodium bicarbonate (20 ml), water (50 ml), dried (frit) and evaporated to dryness. The residual oil was purified on a 20 g Si isolute cartridge using ether as the eluent. The appropriate fractions were evaporated to give the title compound, 510 mg as a colourless solid.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=C[N:3]=1.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[C:22]([OH:25])(=[O:24])[CH3:23]>>[N:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:23]=1[C:22]([OH:25])=[O:24]
Reactant: Cc1ccccn1
Reactant: CC(=O)O
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Product: O=C(O)c1ccccn1
Yield: 77 %

Procedure:
The mixture of 9.3 g (100 mmol) of 2-methylpyridine, 1.6 g (10 mmol) of N-hydroxyphthalimide, 0.15 g (0.5 mmol) of cobalt(II)acetylacetonato, 250 mL of acetic acid was reacted at 100° C. for 6 hours in an atmosphere of oxygen to obtain 2-pyridinecarboxylic acid (picolinic acid: yield 77%) with 2-methylpyridine conversion of 82%. From the reaction mixture, acetic acid was distilled off. 400 mL of benzonitrile and 400 mL of water were added thereto, shaken sufficiently, and allowed to stand to be separated into two liquid phases. To the resultant organic layer was further added 400 mL of water, shaken sufficiently, and allowed to stand to be separated into two liquid phases. The aqueous layer and the organic layer were analyzed by a liquid chromatography, and as a result, the extraction ratio of N-hydroxyphthalimide (on basis of N-hydroxyphthalimide contained in the reaction mixture) into the organic layer was 83%, the extraction ratio of phthalimide into the organic layer was 85%, the extraction ratio of phthalic acid into the organic layer was 66%, and the extraction ratio of cobalt(II)acetylacetonato (on basis of cobalt(II)acetylacetonato contained in the reaction mixture) into the aqueous layer was 97%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10](=[O:23])[C:11]2[S:18][C:17]([CH3:19])=[C:16]3[C:12]=2[CH2:13][C@H:14]2[C:20]([CH3:22])([CH3:21])[C@H:15]23)[CH:5]=[C:4]([CH3:24])[C:3]=1[CH2:25][CH2:26][C:27]([OH:29])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:61]([CH2:63][NH2:64])[OH:62]>CN(C=O)C.C(#N)C.C(O)=O>[CH3:24][C:4]1[CH:5]=[C:6]([CH2:8][CH2:9][C:10](=[O:23])[C:11]2[S:18][C:17]([CH3:19])=[C:16]3[C:12]=2[CH2:13][C@H:14]2[C:20]([CH3:22])([CH3:21])[C@H:15]23)[CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:25][CH2:26][C:27]([NH:64][CH2:63][CH2:61][OH:62])=[O:29]
Reactant: NCCO
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=CO
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1CCC(=O)NCCO
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a solution of 3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenyl}-propionic acid (10 mg, 22 μmol) in DMF (0.5 mL), TBTU (8 mg, 24 μmol) and DIPEA (10 mg, 72.6 μmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (7 mg, 110 μmol) is added. Stirring is continued for 16 h at rt. The mixture is diluted with acetonitril (0.5 mL) and formic acid (25 μL) and separated by prep. HPLC (Waters SymmetryC18 19×50 mm 5 μm, 80% to 0% water (0.5% HCOOH) in acetonitrile) to give 3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenyl}-N-(2-hydroxy-ethyl)-propionamide (7 mg) as a colourless resin; LC-MS: tR=1.03 min, [M+1]+=454.35.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[CH3:22][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CN1CCCCC1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCCC1CN1CCNCC1
Reaction time: 48 h
Yield: 133.3 %

Procedure:
1 ml of a 4M solution of HCl in dioxane is added to a solution of 3.28 g of the compound obtained in step 6.3, in 1 ml of dioxane. The medium is stirred at AT for 48 h. The medium is filtered, and the solid is rinsed with ether and then dried, to give 2.9 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20]Br)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: Fc1ccc(OCCBr)cc1
Product: Cc1cc(C)n2nc(SCCOc3ccc(F)cc3)nc2n1
Yield: 57 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine-2-thiol and 4-fluorophenoxy-ethylbromide in 57% yield; EM (calc.): 318.1; MS (ESI) m/e: 319.1 (M+H)+. NMR (DMSO-d6, 400 MHz) δ ppm: 7.11 (m, 3H), 7.00 (m, 2H), 4.31 (t, 2H), 3.59 (t, 2H), 2.67 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@@H:7]([NH:11]C(=O)OCC1C=CC=CC=1)[CH:8]([CH3:10])[CH3:9].O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:26][C:25]1[C:3]2[C:2](=[CH:24][CH:23]=[CH:22][C:4]=2[O:5][CH2:6][C@@H:7]([NH2:11])[CH:8]([CH3:9])[CH3:10])[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CC(C)[C@@H](COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N

Procedure:
Prepared as in Example 2a from (S)-benzyl 1-(3-amino-2-cyanophenoxy)-3-methylbutan-2-ylcarbamate (Example 95c) and ethyl 3-oxobutanoate as brown solid (79%). MS 332 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(Cl)Cl>C1(C)C(C)=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:15]=[C:16]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccccc1Nc1cccc(Br)c1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: Brc1cccc(-n2c(-c3ccccc3)nc3ccccc32)c1

Procedure:
2.1 g (5.7 mmol) of N-[2-(3-bromophenylamino)phenyl]benzamide was suspended in 30 mL of xylene. After the addition of 0.6 g (2.9 mmol) of p-toluenesulfonic acid monohydrate, the mixture was subjected to azeotropic dehydration under heat reflux for 3 hours. After allowing the reaction solution to cool, ethyl acetate, methylene chloride, and water were added to the reaction solution, and an insoluble component was removed by filtration. The organic phase was extracted from the mother filtrate, washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-(3-bromophenyl)-2-phenyl-1H-benzimidazole.