Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[CH:7]([C:8]([OH:10])=O)[C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13]1>>[C:19]1([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:8]([CH:7]3[C:4]4[CH2:5][CH2:6][C:1]3=[CH:2][CH:3]=4)=[O:10])[CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C1C2=CC=C1CC2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1C2=CC=C1CC2

Procedure:
7-Norbornadienecarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-7-norbornadienecarboxamide.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH3:13]O>>[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:13])=[O:9]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(N)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a solution of saturated HCl in CH3OH (20 mL) at RT was slowly added 5-amino-2-hydroxybenzoic acid (2 g, 13.06 mmol). The resulting mixture was stirred at (RT, 16 h) and then heated (reflux, 24 h). The mixture was cooled and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3. The organic solution was dried over MgSO4, filtered, concentrated under reduced pressure to afford methyl 5-amino-2-hydroxybenzoate as a pale yellow solid (1.72 g, 78.5%). Mass calculated for C8H9NO3=167.16. found: [M+H]+=168.2.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:39])[CH2:36][CH2:37][CH3:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 82.2 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by butyric acid (27 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction, was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-(cis-4-Butyrylamino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (89 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([N:15]([CH3:14])[C@H:16]2[CH2:35][N:20]3[C:21]4[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]3[CH2:18][CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C(C)(C)c1ccc(F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 2-(4-fluorophenyl)-2-methylpropanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 423.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1>C1C=CC=CC=1>[C:2](=[C:3]1[CH2:4][C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]1=[O:1])([CH3:12])[CH3:7]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)=C1Cc2ccccc2C1=O

Procedure:
The reaction mixture was dissolved in 300 ml of benzene and 4.2 g of p-toluenesulfonic acid monohydrate was added to the solution and refluxed for 2 hours for component distillation. The product was used in the subsequent reaction without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([F:14])[CH2:9]2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[F:14][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCC(F)C1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCC(F)C3)c2)CC1
Temperature: 80 °C
Yield: 93 %

Procedure:
A solution of 1-(5-chloro-2-nitro-phenyl)-3-fluoro-piperidine (as prepared in the previous step, 0.44 g, 1.7 mmol) in N-methylpiperazine (2 mL) was heated to 80° C. for 18.5 h. The reaction was cooled to room temperature, diluted with CH2Cl2 and washed with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.50 g, 93%) as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.00 (d, 1H, J=9.2 Hz), 6.44 (dd, 1H, J=9.2 Hz, J=2.8 Hz), 6.34 (d, 1H, J=2.8 Hz), 4.91-4.71 (m, 1H), 3.54-3.44 (m, 1H), 3.41-3.36 (m, 4H), 3.18-3.10 (m, 1H), 3.02-2.94 (m, 1H), 2.87-2.80 (m, 1H), 2.5-2.52 (m, 4H), 2.35 (s, 3H), 1.82-1.66 (m, 4H). LC-MS (ESI, m/z): Calcd. for C16H23FN4O2 323.2 (M+H), found 323.2.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH:5]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:6][C:7]1[C:8]([CH2:16]Cl)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[NH:18][CH:5]1[C:4](=[O:3])[N:34]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:16][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)CN
Reactant: COC(=O)C(Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)CN1Cc2c(ccc3[nH]ncc23)CC(NC(=O)OCc2ccccc2)C1=O

Procedure:
In a manner similar to [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamic acid benzyl ester, the title compound was prepared by treating 2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionic acid methyl ester, hydrochloride with isobutylamine followed by treatment with acetic acid in refluxing toluene to give (9-Isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester in 91% yield. MS (ESI) 407 (M+H); Rf=1.58.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[NH:10][C:11]3=[O:16])[C:7]=2[C:6]([CH3:18])=[CH:5][C:4]=1[O:19][CH3:20].[CH2:21](I)[CH3:22]>>[CH2:21]([N:10]1[C:9](=[O:17])[CH:8]2[CH:12]([CH2:13][CH2:14][C:15]3[C:3]([O:2][CH3:1])=[C:4]([O:19][CH3:20])[CH:5]=[C:6]([CH3:18])[C:7]=32)[C:11]1=[O:16])[CH3:22]
Reactant: CCI
Reactant: COc1cc(C)c2c(c1OC)CCC1C(=O)NC(=O)C21
Product: CCN1C(=O)C2CCc3c(OC)c(OC)cc(C)c3C2C1=O

Procedure:
Using the procedure as described for Example 64, but starting with 3,3a,4,5-tetrahydro-6,7-dimethoxy-9-methyl-1H-benz[e]isoindole-1,3-(2H)-dione, and using ethyl iodide in place of methyl iodide afforded the desired compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:11]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH:12]2[N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:14](=[O:33])[C:15]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=2[S:18](=[O:32])(=[O:31])[N:17]=1>CN(C)C=O>[OH:9][C:10]1[CH:11]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH:12]2[N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:14](=[O:33])[C:15]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([N:26]([CH3:1])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=2[S:18](=[O:31])(=[O:32])[N:17]=1
Reactant: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Potassium carbonate (0.067 g, 0.488 mmol) and iodomethane (0.017 mL, 0.268 mmol) were added sequentially to a solution of N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 33b, 0.128 g, 0.244 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between ethyl acetate (30 mL) and water (2×20 mL). The organic layers were washed with saturated aqueous brine solution (50 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 30-80% ethyl acetate in hexanes) to afford the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.045 g, 0.084 mmol, 34%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.00 (d, 6H, J=7.1 Hz), 1.40-2.24 (m, 14H), 2.88 (d, 3H, J=2.1 Hz), 2.94-3.09 (m, 1H), 3.30-3.53 (m, 2H), 3.37 (d, 3H, J=3.1 Hz), 3.95-4.09 (m, 1H), 7.17-7.23 (m, 1H), 7.67-7.73 (m, 1H), 7.77-7.80 (m, 1H). LC-MS (ESI) calcd for C24H34N4O6S2 538.19, found 539.4 [M+H+].
Reaction SMILES: C[C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:14]=[N:15][NH:16][C:17]([O:19]C)=O.Cl[C:22]1C=CC=CC=1Cl>>[CH3:22][C:14]1[C:3]2[N:4]([C:5]([C:7]3[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=3)=[N:6][CH:2]=2)[C:17](=[O:19])[NH:16][N:15]=1
Reactant: COC(=O)NN=Cc1nc(-c2cccc(C)c2)[nH]c1C
Reactant: Clc1ccccc1Cl
Product: Cc1cccc(-c2ncc3c(C)n[nH]c(=O)n23)c1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A mixture of 3-[(5-methyl-2-m-tolyl-4-imidazolyl)-methylene]carbazic acid, methyl ester (5.1 g, 0.019 mole) and o-dichlorobezene (75 ml) is heated slowly (45 minutes) to reflux, refluxed for 1.5 hours, then stirred at room temperature over night (appr. 15-16 hours). The reaction mixture is filtered to afford 3.9 g (0.016 mole) title product. Recrystallization from o-dichlorobenzene yields partially solvated product, m.p. 188°-198° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[N:16]([CH3:21])[C:15](=[O:22])[CH:14]=1>>[NH2:16][C:15]1[C:14]([C:13]#[N:12])=[C:7]([C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH3:11])[C:14]2[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:13]=2[N:12]=1
Reactant: COc1ccc(F)cc1C=O
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Product: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
7-amino-5-(5-fluoro-2-methoxyphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (70a) was prepared by the reaction of 5-fluoro-2-methoxybenzaldehyde and 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, according to procedures described in the synthesis of Compound 56. MS [m+H] calc'd C17H15FN5O3 356; found 356.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8]
Reactant: Cc1ccccc1N
Reactant: O=C(O)c1ncc[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1NC(=O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.52 g, 4.64 mmol) in DMF (20 mL) was added o-toluidine (0.50 mL, 4.64 mmol), EDCHCl (1.35 g, 6.96 mmol) and HOBt (0.94 g, 6.96 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, it was poured into water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated to dryness. The crude product was purified by flash chromatography (2% to 3% MeOH/DCM) to yield 0.93 g (99%) of the title compound as a beige solid.
Reaction SMILES: Cl[S:2]([C:5]1[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=1)(=[O:4])=[O:3].Cl.[CH:16]12[NH:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(CC)CC)C>C(OCC)(=O)C>[CH:20]12[N:23]([S:2]([C:5]3[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=3)(=[O:4])=[O:3])[CH:16]([CH2:22][CH2:21]1)[CH2:17][CH2:18][CH2:19]2
Reactant: C1CC2CCC(C1)N2
Reactant: CN(C)C(=O)n1cnc(S(=O)(=O)Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1cnc(S(=O)(=O)N2C3CCCC2CC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A mixture of 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 54-a) (470 mg), 8-azabicyclo[3.2.1]octane hydrochloride (350 mg), triethylamine (0.7 ml), and ethyl acetate (10 ml) was stirred overnight at room temperature. The reaction solution was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 50 to 100% ethyl acetate/hexane to yield the title compound (150 mg).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>O>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:29])=[CH:26][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(OC2CCCC2)nc1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1ccc(OC2CCCC2)nc1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.42 g (2.1 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.42 g (2.0 mmol) of 6-cyclopentyloxynicotinic acid, followed by the addition of 0.35 g (4.2 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether: hexane=1:7) to obtain 0.44 g (yield: 70%) of 4,4-difluoro-3-methyl-3-butenyl 6-cyclopentyloxynicotinate.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2([CH3:15])[CH3:14])=[C:7]([C:16]2([CH2:19][CH:20]=O)[CH2:18][CH2:17]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([CH:27]=[C:28]([CH3:34])[CH2:29]P(=O)([O-])[O-])=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:26])[CH:27]=[C:28]([CH3:34])[CH:29]=[CH:20][CH2:19][C:16]1([C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][C:11]3([CH3:14])[CH3:15])[CH2:18][CH2:17]1)[CH3:23]
Reactant: CC(C)(C)c1cc2c(c(C3(CC=O)CC3)c1)CCC2(C)C
Reactant: CCOC(=O)C=C(C)CP(=O)([O-])[O-]
Product: CCOC(=O)C=C(C)C=CCC1(c2cc(C(C)(C)C)cc3c2CCC3(C)C)CC1
Yield: 62.5 %

Procedure:
The above unsaturated alcohol (16) (30 mg, 0.16 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 33 mg of [1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropyl]-ethanol (17) as a pale yellow oil in 67% yield that was used directly for the next step. The above cyclopropyl alcohol (33 mg, 0.15 mmol) was oxidized as described in Example 1 to give 32 mg of 1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropaneacetaldehyde (18) as a clear oil in 100% yield. The above cyclopropyl aldehyde 18 (32 mg, 0.15 mmol) and 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (200 mg, 0.77 mmol) were condensed as described for Example 1 to give 37 mg of ethyl-6-[1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropyl]-3-methyl-2,4-hexadienoate (19) as a pale yellow oil in 69% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[Cu][C:17]#[N:18].ClCCl>CN(C=O)C>[C:17]([C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1)#[N:18]
Reactant: O=C1Nc2ccc(Br)cc2C2CCCC12
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)C1CCCC1C(=O)N2
Yield: 38.3 %

Procedure:
A solution of 8-bromo-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (230 mg, 0.86 mmol) in DMF (20 ml) is mixed with copper(I) cyanide (77 mg, 0.86 mmol) and refluxed for 16 hours. The batch is diluted dichloromethane, washed with saturated NH4Cl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Purification on silica gel with ethyl acetate-hexane yields 70 mg (38%) of product.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>C1COCC1>[CH:4]1[C:5]2[CH:6]([CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[OH:29])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2c(c1)Cc1ccccc1C2
Reactant: COc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2c3ccccc3Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cool a THF (50 mL) solution of 9,10-dihydroanthracene (5.10 g, 28 mmol) to 0° C. and add 1.6M n-BuLi (19 mL, 30 mmol) slowly. After 30 minutes, add m-anisaldehyde (3.4 mL, 28 mmol) to the dark brown solution. Allow the reaction to slowly warm to ambient temperature and then carefully quench with aqueous saturated NH4Cl. Shake the entire reaction with water/EtOAc and dry the organic layer (MgSO4). Concentrate under reduced pressure to give 9.4 g light tan oil. Purify by column chromatography using 25% EtOAc/hexane to give 4.7 g (53%) as a colorless oil that rapidly crystallized, mp 105.9° C. HPLC shows 94% purity.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:26]=[N:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[CH:23][CH:22]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:26]=[N:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNCC2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butyl 4-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)piperidine-1-carboxylate (0.18 g, 0.40 mmol) in DCM (3 mL) at 0° C. The reaction was stirred for 1 h at RT. The reaction mixture was added to an aqueous solution of NaOH (1 M) and the aqueous phase was extracted with chloroform/propan-2-ol (3:1). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(piperidin-4-yloxy)pyridazine (0.14 g, 100%) as a colorless solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:22]#[C:23][CH3:24]>C(N(CC)CC)C.C(OCC)C.[Cu]I>[CH:11]([O:10][C:4]1[C:3]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([C:22]#[C:23][CH3:24])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([CH3:13])[CH3:12]
Reactant: COc1ccc(I)c(SCc2ccccc2)c1OC(C)C
Reactant: C#CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC#Cc1ccc(OC)c(OC(C)C)c1SCc1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A mixture of the product of Step A (0.123 g; 0.296 mmol), Cl2Pd(PPh3)2 (0.040 g; 0.057 mmol), CuI (0.014 g; 0.073 mmol) in anhydrous triethylamine (3 ml) was cooled to −40° C., degassed under reduced pressure and saturated with dry N2. The propyne gas (0.45 g; 11.2 mmol) was added to it at −40° C. The reaction flask was sealed with septum and allowed to warm up to room temperature and stirred for 3 h at room temperature and diluted to 20 ml with diethyl ether and solid precipitated, filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue, purified by flash column chromatography (SiO2, hexane, hexane/ethyl acetate, 9:1) to give the title compound (0.065 g; 67% yield) as colourless syrup. 1H-NMR (CDCl3) 1.26 (d, 6H, J=6.17 Hz); 2.09 (s, 3H); 3.79 (s, 3H); 4.2 (s, 2H); 4.44 (m, 1H, J=6.17 Hz); 6.73 (d, 1H, J=8.53 Hz); 7.12 (d, 1H, J=8.53 Hz); 7.15-7.4 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[CH:3]=1)[CH2:8][Br:10]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
5-Bromo-m-xylene (10.0 g; 54.0 mmol), N-bromosuccinimide (9.63 g; 54.0 mmol), and benzoyl peroxide (150 mg) were added to benzene (100 ml), and the mixture was heated under reflux for 2.5 hours. The resultant mixture was left to cool to room temperature, and insoluble matter was filtered off, followed by washing with benzene. The filtrate was evaporated under reduced pressure, and the residue was taken up in n-hexane. The mixture was left to stand for 30 minutes, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:0→20:1), to thereby yield 9.44 g of the target compound (yield: 66.3%).