Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH2:13])=[NH:12])[S:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH2:18]([N:20]([CH2:33][CH3:34])[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=S)=[CH:26][CH:25]=1)[CH3:19].CI>CN(C)C=O.O>[NH2:12][C:11]1[N:10]=[C:8]2[N:7]([C:31](=[N:30][C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][N:20]([CH2:18][CH3:19])[CH2:33][CH3:34])=[CH:29][CH:28]=3)[N:13]=1)[C:6]1[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[S:9]2
Reactant: COc1ccc2nc(NC(=N)N)sc2c1
Reactant: CCN(CC)CCOc1ccc(N=C=S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(N=c2nc(N)nc3sc4cc(OC)ccc4n23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
6-Methoxybenzothiazol-2-ylguanidine (0.2 g) was added to a suspension of sodium hydride (0.022 g=0.044 g of 50% dispersion in oil) in anhydrous dimethylformamide (20 mls) and the resulting mixture was stirred at room temperature for 15 mins. 4-(2-Diethylaminoethoxy)phenylisothiocyanate (0.23 g) was added followed, after 2.5 hrs, by methyl iodide (0.14 g) and the mixture stirred for a further 18 hrs. Water was added to precipitate a yellow solid which was collected by filtration, washed with ethanol and dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulphate and evaporated to give a yellow solid (0.33 g). Recrystallisation of the residue from ethyl acetate gave the desired product as pale yellow crystals (0.08 g) mp 189.5°-191°.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]C)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Temperature: 25 °C

Procedure:
The 4-acetoxy-3,5-di-tert-butylanisole obtained in Example 13 and 1.37 kg (9.14 mol) of sodium iodide were dissolved in 5.0 L of acetonitrile; thereafter, 1.16 L (9.14 mol) of trimethylsilyl chloride was added dropwise and the mixture was refluxed for 8 hours. Thereafter, the reaction mixture was cooled to room temperature, water was added and the organic layer was separated. The organic layer was washed with an aqueous solution of sodium thiosulfate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic layer was recrystallized from an ethanol/water mixed solvent and the crystal was dried to give 1.55 kg of the title compound (92.4% in yield from the 2,6-di-tert-butyl-4-methoxyphenol of Example 13).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[CH:15]=[N:14][N:13]=1>CC#N>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([N:6]1[CH2:5][CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]3[CH2:1]1)=[N:13][N:14]=[CH:15]2
Reactant: O=C1CCC2CNCCN12
Reactant: Clc1ccc2c(Cl)nncc2c1
Solvent: CC#N
Product: O=C1CCC2CN(c3nncc4cc(Cl)ccc34)CCN12
Temperature: 135 °C
Yield: 19.5 %

Procedure:
A mixture of tetrahydropyrrolo[1,2-a]pyrazin-6(1H,2H,7H)-one (Med. Chem. Res., 7:301 (1997); 0.983 g, 7.01 mmol), 1,6-dichlorophthalazine (1.36 g, 6.83 mmol) and TEA (2.00 mL, 14.3 mmol) in 18 mL of CH3CN was heated at 135° C. for 30 min in a microwave oven. The reaction mixture was concentrated onto silica gel and purified using flash chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give 404 mg (20%) an orange foam/amorphous solid. MS m/z: 303.1 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:7]([C:6]2[N:5]([CH3:12])[N:4]=[C:3]([CH3:13])[C:2]=2[Cl:1])=[O:9])=[CH:24][CH:25]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1c(Cl)c(C)nn1C
Reactant: CC(C)(C)c1ccc(CN)cc1
Product: Cc1nn(C)c(C(=O)NCc2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 200 °C
Yield: 69.9 %

Procedure:
A mixture of 2.03 g of ethyl 4-chloro-1,3-dimethylpyrazole-5-carboxylate and 2.45 g of 4-tertbutylbenzylamine was heated at 200° C. for 4 hours under stirring. After cooling to room temperature, the reaction product was purified by silica gel column chromatography to obtain 2.24 g of the compound (No. 36) described in Table 1.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(O)CCCCC1>[Cl:1][C:2]1[C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: C1CNCCN1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OC1CCCCC1
Product: Nc1cc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 14 h
Yield: 84.9 %

Procedure:
Into a solution of 20.02 g of 4,5-dichloro-2-nitroaniline and 8.70 g of piperazine in 100 ml of cyclohexanol, 12.80 g of sodium carbonate was added and stirred at 150° C. for 14 hours. Cooling the reaction liquid to room temperature, water was added and the system was extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate and the solvent was distilled off. Thus obtained residue was washed with diisopropyl ether to provide 21.07 g of 4-chloro-2-nitro-5-(piperazin-1-yl) aniline as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([O:20]C)=[O:19])=[N:10]1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([OH:20])=[O:19])=[N:10]1
Reactant: COC(=O)c1nn(-c2cc(I)ccc2F)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn(-c2cc(I)ccc2F)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
To a suspension of methyl 1-(2-fluoro-5-iodophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (11.3 g, 28.1 mmol) in MeOH (112 mL) was added 1 M NaOH aqueous solution (56 mL) at 0° C. The mixture was stirred at room temperature for 90 min. To the mixture was added 1 M HCl aqueous solution (56 mL) at 0° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 60° C. to yield the title compound (9.96 g, 91% yield) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.88 (3H, s), 7.42 (1H, dd, J=10.6, 8.7 Hz), 8.00 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 8.16 (1H, dd, J=7.2, 2.3 Hz), 8.85 (1H, s), 14.86 (1H, brs).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=2)=[CH:7][CH:8]=1)N.[H][H]>CO.[Ni]>[NH2:1][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2ccc(NN)nn2)cc1OC(C)C
Agent: [Ni]
Solvent: CO
Product: COc1ccc(-c2ccc(N)nn2)cc1OC(C)C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
10 g (36 mmol) of 3-hydrazino-6-[4-methoxy-3-(1-methylethoxy)phenyl]pyridazine are hydrogenated in 100 ml of methanol in the presence of 1 g of Raney nickel with hydrogen under atmospheric pressure at room temperature while stirring efficiently. Starting material is no longer detectable after 4 hours. The solution is filtered to remove catalyst and concentrated in vacuo, and the residue is crystallized from isopropanol/cyclohexane. 4.3 g (46%) of 3-amino-6-[4-methoxy-3-(1-methylethoxy)phenyl]pyridazine of m.p. 184° C. are obtained.
Reaction SMILES: [N:1]([CH2:4][C@:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)([OH:7])[CH3:6])=[N+:2]=[N-:3].[B:15](OC(C)C)(OC(C)C)[O:16]C(C)C.[Li]CCCC>C1(C)C=CC=CC=1>[N:1]([CH2:4][C@@:5]1([CH3:6])[O:7][B:15]([OH:16])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]1=2)=[N+:2]=[N-:3]
Reactant: C[C@@](O)(CN=[N+]=[N-])c1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: C[C@]1(CN=[N+]=[N-])OB(O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
(S)-1-azido-2-(2-bromophenyl)propan-2-ol (8.7 g, 34.0 mmol) and triisopropyl borate (9.4 mL, 40.8 mmol) were dissolved in 170 mL of toluene. The reaction mixture was refluxed with a Dean/Stark apparatus to remove the toluene and the residue was dissolved in 150 mL of dry THF. This solution was cooled to −78° C. and BuLi (25M in Hexanes, 15.6 mL, 39.1 mmol) was added dropwise and stirred for 30 min. The reaction mixture was warmed to room temperature and allowed to stir for 3 hrs before being quenched with 50 mL of 6M HCl and concentrated under vacuum. This was extracted 3× with 100 mL of DCM. The combined organic layers were dried over MgSO4 and evaporated under vacuum. Purified by silica gel chromatography (20-30% Et2O/petroleum ether) to give 2.1 g (30%) of (S)-3-(azidomethyl)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol as a dark yellow oil.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1>>[O:37]=[S:34]1(=[O:38])[CH2:35][CH2:36][N:31]([C:2]2[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=4)[N:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[CH:11]=3)=[O:7])=[CH:4][N:3]=2)[CH2:32][CH2:33]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(N2CCS(=O)(=O)CC2)nc1

Procedure:
6-(1,1-Dioxo-1-thiomorpholin-4-yl)-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-nicotinamide was prepared starting from 6-chloro-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (example I-105) and thiomorpholine-1,1-dioxide. MS calcd. for C26H22F2N4O4S [(M+H)+] 525.1, obsd. 525.2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1C=CC=CC=1>[C:12]([O:4][CH2:3][CH2:2][Br:1])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: OCCBr
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCBr
Temperature: 25 °C
Yield: 60.4 %

Procedure:
An egg-plant type flask which contained benzene (500 ml) was charged with 2-bromoethanol (46.7 g, 0.37 mol) and triethylamine (29.1 g, 0.29 mol) and was capped with a rubber plug. Methacryloyl chloride (30 g, 0.29 mol) was added to the flask in ice water, using a syringe while being stirred with a stirrer. The stirring was continued for some time, and then, the mixture was warmed to a room temperature and was stirred overnight. Triethylamine hydrochloride was removed by suction filtration, and the mixture was washed three times with water (300 ml) to extract the unreacted substance. The mixture was transferred to a conical flask and was dried over anhydrous sodium sulfate. The mixture was concentrated by an evaporator under reduced pressure and purified by vacuum distillation to give a colorless and clear liquid (33.8 g) (yield: 61%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][CH:42]=1)[CH2:27][CH2:28][N:29]([CH2:37][CH2:38][OH:39])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][CH:42]=1)[CH2:27][CH2:28][N:29]([CH2:37][CH:38]=[O:39])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N(CCO)CCc1cccc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC=O)CCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of Dess-Martin periodinane (0.51 g, 0.0012 mol) in anhydrous CH2Cl2 (10 mL) was added a solution of tert-butyl 3-fluorophenethyl(2-hydroxyethyl)carbamate (V-5b, 0.28 g, 0.001 mol) in anhydrous CH2Cl2 (5 mL) via a cannula, and the reaction mixture was stirred at room temperature for 18 h under a N2 atmosphere. Na2S2O3 (1 M, 10 mL) was then added to the reaction mixture. After being stirred for 10 min, the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (15 mL×3). The combined organic layers were washed with 5% aqueous NaHCO3 (20 mL) and brine (20 mL), and dried over Na2SO4. The solvent was evaporated. The residue was then purified by column chromatography (silica gel, hexane:EtOAc=7.5:2.5) to afford a colorless oil (XII-8, 0.24 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.CN([CH:29]=[O:30])C.Cl.CCOCC.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:29]=[O:30])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CN(C)C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(C=O)cnc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (0.90 g, 2.91 mmol) in THF (8 mL), cooled at −78° C., is added slowly sec-BuLi (1.4 M in hexane, 4.16 mL, 5.82 mmol). After stirring for 45 minutes, the DMF (0.68 mL, 8.74 mmol) is added at −78° C. The mixture is stirred for 1 hour and quenched with HCl in ether solution (1M, 8.73 mL, 8.73 mmol). The mixture is allowed to warm to room temperature. The reaction mixture is basified with saturated sodium bicarbonate solution to a pH of 8 and extracted with ethyl acetate. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to afford the mixture of the title compounds, which is used for next reaction without any further purification: MS m/z 337.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17][CH2:19][CH2:18][CH3:23])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)O
Solvent: CCCO
Product: CCCOC(=O)c1cc(-c2ccc(Cl)cc2)cnc1C
Yield: 28.2 %

Procedure:
5-(p-Chlorophenyl)-2-methyl-3-pyridine carboxylic acid (2 gm) and p-toluenesulphonic acid (1.69 g) in n-propanol (125 ml) was refluxed for 15 hours. The solution was concentrated and the residue partitioned between methylene dichloride and aqueous sodium carbonate. The organic phase was separated, washed with water, dried and concentrated to an oil which slowly crystallised to give the title compound (0.66 g), m.p. 54°-7°.
Reaction SMILES: [CH:1]1([CH:5]=[C:6]2[CH2:15][CH2:14][C:13]3[CH:12]=[C:11]([C:16]([O:18]C)=[O:17])[CH:10]=[CH:9][C:8]=3[C:7]2=O)[CH2:4][CH2:3][CH2:2]1.Cl.[Cl:22][C:23]1[CH:30]=[C:29]([NH:31][NH2:32])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[Cl:22][C:23]1[CH:30]=[C:29]([N:31]2[CH:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:6]3[C:7]([C:8]4[CH:9]=[CH:10][C:11]([C:16]([OH:18])=[O:17])=[CH:12][C:13]=4[CH2:14][CH2:15]3)=[N:32]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCC2)cc1Cl
Yield: 65 %

Procedure:
The title compound was prepared according to Method B and Method C from methyl 6-(cyclobutylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 19 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1) to give 2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (150 mg, 0.36 mmol, 65% yield) as a yellow solid. The title compound was largely present as (±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.77 (m, 4H), 1.77-1.98 (m, 3H), 2.07-2.18 (m, 1H), 2.51-2.59 (m, 1H), 2.80-2.93 (m, 1H), 2.97-3.07 (m, 1H), 3.44-3.56 (m, 1H), 4.88 (dd, J=9.40, 6.98 Hz, 1H), 7.22 (dd, J=8.86, 1.88 Hz, 1H), 7.42 (d, J=2.15 Hz, 1H), 7.67 (d, J=8.86 Hz, 1H), 7.75-7.83 (m, 2H), 8.01 (d, J=8.06 Hz, 1H). ES-MS m/z 420 (M+H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[CH3:10].Cl.[O-:12][C:13]#[N:14].[K+]>O>[CH3:10][C:5]1[N:4]([CH2:3][CH2:2][NH:1][C:13]([NH2:14])=[O:12])[C:8]([CH3:9])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C)n1CCN
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc(C)n1CCNC(N)=O

Procedure:
6.9 g (0.05 mol) of 1-(2-aminoethyl)2,5-dimethylpyrrole are dissolved in 8 ml of water. While cooling, 5 ml of concentrated hydrochloric acid are slowly added dropwise, and then 4.9 g (0.05 mol) of potassium cyanate, dissolved in 30 ml of water, are added dropwise. The precipitated solid is filtered off with suction and recrystallized from toluene/ethyl acetate. Yield: 3.8 g (42% of theory), Melting point: 139°-141° C. Elemental analysis: C9H15N3O (181.24) calculated: C 59.6 H 8.3 N 23.2 0 8.8 found: C 59.2 H 8.2 N 22.8 0 9.1
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:15]([OH:17])=O)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O[N:42]=[C:43]([C:45]1[CH:62]=[CH:61][C:48]([CH2:49][N:50]2[CH2:53][CH:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:51]2)=[CH:47][CH:46]=1)[NH2:44].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1>C(#N)C>[CH:1]([C:4]1[C:5]([C:15]2[O:17][N:44]=[C:43]([C:45]3[CH:46]=[CH:47][C:48]([CH2:49][N:50]4[CH2:51][CH:52]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH2:53]4)=[CH:61][CH:62]=3)[N:42]=2)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Reactant: CC(C)c1c(C(=O)O)noc1-c1ccccn1
Agent: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)c1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccn1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4-isopropyl-5-(pyridin-2-yl)isoxazole-3-carboxylic acid salt (10.4 mg, approx. 0.045 mmol), HOBt (12.34 mg, 0.081 mmol), and diisopropylethylamine (0.031 mL, 0.179 mmol) in acetonitrile (1 mL) was added EDC (20.2 mg, 0.105 mmol) and tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (13.68 mg, 0.045 mmol). The reaction mixture was stirred at 80° C. for 5 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification on a preparative TLC plate with ethyl acetate afforded tert-butyl 1-(4-(5-(4-isopropyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.C[O:9][C:10]1[C:11](=[O:28])[C:12]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1.O>C(#N)C>[OH:9][C:10]1[C:11](=[O:28])[C:12]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1
Reactant: COc1cn(-c2ccccc2)nc(-c2ccnn2C)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Temperature: 25 °C
Yield: 35.4 %

Procedure:
To a solution of sodium iodide (7.49 g) in acetonitrile (300 mL) was added chlorotrimethylsilane (6.35 mL) at room temperature with stirring, and the mixture was stirred for 30 min. Then, 5-methoxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (2.82 g) was added, and the mixture was stirred for 30 min at the same temperature and further refluxed for 7 hr. The reaction mixture was allowed to cool to room temperature, poured into water and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration, washed successively with water, methanol, and diisopropyl ether, and dried to give the title compound (0.95 g) as pale-yellow needles. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.70 g) as pale-yellow needles.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C:9]1([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2([C:24]([O:26][C:27](C)(C)[CH3:28])=[O:25])[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]>>[C:2]([O:6][C:7]([C:9]1([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:23])([CH3:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Product: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC1(C(=O)OC(C)(C)C)CC1

Procedure:
Compound 6c was prepared likewise Method C starting from 108a (20.5 g, 55.9 mmol), 105a (18.11 g, 55.9 mmol) and KOtBu (6.57 g, 58.7 mmol) to give a yellow oil (31.79 g). Part of this oil (30.63 g) was treated with cone aqueous HCl (23 mL), as described for 106d, to give, after purification by column chromatography (silica, heptane:EtOAc=40:1), 106c (9.83 g, >90% pure by NMR, 43%) as a colorless oil. 1H NMR: δ 4.09 (q, J=7.2 Hz, 2H), 2.38 (t, J=7.2 Hz, 4H), 1.62-1.35 (m, 10H), 1.41 (s, 9H), 1.26-1.17 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (s, 6H), 1.09 (dd, J=6.9, 4.2 Hz, 2H), 0.59 (dd, J=6.3, 3.6 Hz, 2H). 13C NMR: δ 210.5, 177.4, 174.0, 79.8, 60.2, 42.8, 42.6, 42.1, 40.5, 34.0, 28.2 (3×), 27.5, 25.2 (2×), 24.7, 24.3, 24.2, 24.1, 15.3 (2×), 14.4.