Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([N:27]4[CH2:31][CH2:30][CH:29]([CH3:32])[C:28]4=[O:33])=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl>C1COCC1.O>[C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([N:27]4[CH2:31][CH2:30][CH:29]([CH3:32])[C:28]4=[O:33])=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(N4CCC(C)C4=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(N4CCC(C)C4=O)c(C=O)nc32)ncc1C#N
Reaction time: 4 h

Procedure:
To a solution of (racemic) N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(3-methyl-2-oxopyrrolidin-1-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 330, 63 mg, 0.120 mmol) in THF (0.9 ml) and water (0.3 mL) was added 37% aqueous HCl (0.1 mL, 3.29 mmol) at room temperature and the reaction mixture was stirred for 4 h. The reaction mixture was quenched by the addition of saturated aqueous Na2CO3 and diluted with DCM. Phases were separated and the water phase was extracted with DCM. The combined organic layers were dried using Na2SO4, filtered and solvents were concentrated. The crude product was precipitated from DCM and EtOAc, filtered and dried to yield the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20]([CH2:22][NH2:23])[CH:19]=[N:18]1.C(N(CC)CC)C.O>CS(C)=O>[CH3:16][N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(CN)cn1
Reactant: CCOC(=O)c1cc(Cl)n2nccc2n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc(NCc2cnn(C)c2)n2nccc2n1
Temperature: 100 °C

Procedure:
To a solution of ethyl 7-chloropyrazolo[1,5-a]pyrimidine-5-carboxylate (2.0 g, 8.9 mmol) in 15 mL DMSO were added (1-methyl-1H-pyrazol-4-yl)methanamine and triethylamine (2.69 g, 3.71 mL, 26.6 mmol), and the mixture was heated at 100° C. under microwave irradiation for 15 minutes. The reaction was then added to water (50 mL), and the precipitate was collected by filtration. The resulting white solid was carried forward without further purification. MS (Electrospray): m/z 301.2 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:5][CH2:4][N:3]1[C:21]([C@@H:23]1[CH2:27][C@H:26]([S:28][C:29]2[C@H:30]([CH3:53])[C@@H:31]3[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]3[C:33]=2[C:34]([O:36]CC2C=CC([N+]([O-])=O)=CC=2)=[O:35])[CH2:25][N:24]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:22].[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:21]([C@@H:23]1[CH2:27][C@H:26]([S:28][C:29]2[C@H:30]([CH3:53])[C@@H:31]3[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]3[C:33]=2[C:34]([OH:36])=[O:35])[CH2:25][NH:24]1)=[O:22]
Reactant: C[C@@H]1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)[C@@H]1C[C@H](SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CNCCN1C(=O)[C@@H]1C[C@H](SC2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)CN1

Procedure:
132 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(2R)-2-methyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] was dissolved in 3 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 160 μl of 1N aqueous hydrochloric acid were added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 150 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 23 mg of the title compound as a powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12]([C:16]([OH:18])=O)=[CH:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.Cl.[CH3:35][NH:36][O:37][CH3:38]>ClCCl.CN(C=O)C>[CH3:38][O:37][N:36]([CH3:35])[C:16]([C:12]1[CH2:11][CH:10]2[CH:14]([CH2:15][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH:13]=1)=[O:18]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC2C=C(C(=O)O)CC2C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1=CC2CN(C(=O)OC(C)(C)C)CC2C1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]-oct-6-ene-7-carboxylic acid (0.080 g, 0.32 mmol) in dichloromethane (3.0 mL) was added oxalyl chloride (0.20 g, 1.6 mmol), followed by a drop of DMF. After stirring for 1 h, the the reaction mixture was concentrated in vacuo, and the residual acid chloride was dissolved in acetonitrile (3.0 mL). DIPEA (0.17 mL, 0.96 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.042 g, 0.43 mmol) were added, and the reaction was stirred at ambient temperature for 1 h. The solvent was evaporated, and the residue was purified by silica gel column chromatography, eluting with 80-90% ethyl acetate in hexanes, to obtain 0.078 g (82% yield) of N-methoxy-N-methyl-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-ene-7-carboxamide, as an oil. This was dissolved in dichloromethane (3.0 mL), treated with TFA (2.0 mL) and stirred at ambient temperature for 1 h. The volatiles were evaporated, and the residue was vacuum dried to obtain 0.07 g of N-methoxy-N-methyl-3-azabicyclo[3.3.0]oct-6-ene-7-carboxamide trifluoroacetate, as an oil (1H NMR (CD3OD, 300 MHz): δ 6.29 (bs, 1H), 3.80-3.89 (m, 1H), 3.88 (s, 3H), 3.54-3.41 (m, 2H), 3.38-3.30 (m, 1H), 3.26 (s, 3H), 3.22-3.03 (m, 3H), 2.66-2.59 (m, 1H); MS (m/z): 197 (M+1)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][S:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[OH:29]O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][S:21](=[O:29])[CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCSCC2)C1
Reactant: OO
Solvent: O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCS(=O)CC2)C1
Reaction time: 8 h

Procedure:
To a stirred solution of 4-hydroxy-5-oxo-1-(2-thiomorpholin-4-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (108 mg, 0.243 mmol) in water (20 mL) was added 30% hydrogen peroxide (0.3 mL). After stirring overnight the reaction mixture was lyophilized to give the title compound as a white powder. 1HNMR (500 MHz, CDCl3) δ: 7.42 (1H, d, J=8.5 Hz), 7.34 (1H, s), 7.10 (1H, d, J=8.2 Hz), 4.59 (2H, s), 4.28 (2H, s), 3.89 (2H, t, J=5.8 Hz), 3.74–3.70 (2H, m), 3.63 (2H, t, J=11.9 Hz), 3.29–3.24 (2H, m), 3.18 (2H, t, J=11.9 Hz), 3.07–2.99 (2H, m), 3.01 (3H, s). HRMS calcd for C19H24Cl2N3O4S (M+H): 460.0865. found: 460.0884.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:30]([NH:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(CNC(=O)c2ccccc2)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (75 mg), benzoic acid (27.9 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (54.7 mg) and 1-hydroxybenotriazole (38.5 mg) in dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:1].[ClH:14].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:31][CH:30]=3)[CH2:21][CH2:22]2)[OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC(Nc1ccc(Cl)c(Cl)c1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 52.2 %

Procedure:
The procedure described in Example 2 was followed, using 1.6 g of 3,4-dichlorophenyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.9 g of triethylamine and 50 ml of methylene chloride, to give 1.2 g (26% of theory) of N-(3,4-dichlorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 227°-230° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].IC.[C:25](=O)([O-])[O-].[K+].[K+]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@@H:12]1[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13]1)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn([C@@H]2CCNC2)c2ccc(I)cc2c1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1cn([C@@H]2CCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
To a solution of (R)-ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Intermediate 110, 282 mg, 0.68 mmol, 1 equiv.) in THF (7 mL) was added iodomethane (0.0471 mL, 0.75 mmol, 1.1 equiv.) followed by potassium carbonate (378 mg, 2.74 mmol, 4 equiv.). This was stirred at 60° C. for 1 d. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organics were concentrated to provide (R)-ethyl 6-iodo-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a light yellow solid (282 mg, >99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].[Br:12]N1C(=O)CCC1=O>O1CCCC1.O>[Br:12][C:5]1[C:4]([OH:11])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][CH:6]=1
Reactant: COc1cccc(O)c1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)c(O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2,3-dimethoxy-phenol (6 g, 38.70 mmol) in tetrahydrofuran (30 mL) at 25° C., was added N-bromosuccinimide (6.89 g, 38.70 mmol) and the resultant reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 6-Bromo-2,3-dimethoxyphenol as a solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24].O>CCO>[CH3:22][N:23]([CH3:24])[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)s1)c1nc(C(F)(F)F)nc2ccsc12
Reactant: CNC
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C(=O)c2nc(C(F)(F)F)nc3ccsc23)s1
Yield: 42 %

Procedure:
A suspension of 5-bromo-2-thienyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone (0.3 g, 0.76 mmol) in EtOH (20 mL) was treated with 40% aqueous dimethylamine (5 mL), refluxed for 1 h, cooled, treated with water (25 mL), concentrated in vacuo and the aqueous mixture extracted with EtOAc (2×25 mL), the combined extracts washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The resulting red oil was purified by chromatography [SiO2; heptane-EtOAc (1:1)] to give the title compound (0.115 g, 42%) as a red solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:24]([CH2:25][CH3:26])=[CH:23][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH2:16])=[CH:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2].C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]1[C:24]([CH2:25][CH3:26])=[CH:23][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])=[CH:14][N:13]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3N)[nH]c2cc1CC
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)[nH]c2cc1CC
Reaction time: 48 h
Yield: 83.9 %

Procedure:
A solution of 3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine [0.3 g, Reference Example 49(a)] and triethylamine (0.8 mL, excess) in tetrahydrofuran (20 mL) was treated dropwise with cyclopropanecarbonyl chloride (0.3 g, 2.4 mmol). This mixture was stirred for 48 hours then diluted with aqueous sodium bicarbonate solution (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was dissolved in tetrahydrofuran (50 mL). This solution was treated with a solution of potassium hydroxide (1.1 g) in ethanol (10 mL) and the mixture was stirred for 2 hours, then poured into water (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel eluting with a mixture of heptane and ethyl acetate (1/1, v/v) to give cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide (0.3 g) as an off-white solid. LC-MS (Method E): RT 2.99 minutes, 424 (M+H)+.
Reaction SMILES: [N:1]1([C:16]([O:18][CH:19]2[CH:26]3[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:28][CH:20]2[CH2:21]4)[CH2:25]3)=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH2:29]([O:31][C:32]([C@@H:34]1[CH2:36][C@H:35]1[C:37](O)=[O:38])=[O:33])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[CH2:29]([O:31][C:32]([C@@H:34]1[CH2:36][C@H:35]1[C:37]([N:8]1[CH2:7][C:4]2([CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]3[CH:20]4[CH2:28][CH:24]5[CH2:23][CH:22]([CH2:27][CH:26]3[CH2:25]5)[CH2:21]4)=[O:17])[CH2:2][CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:38])=[O:33])[CH3:30]
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
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: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)N1Cc2ccccc2C2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)C1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
2-Adamantyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (12 mg, 0.025 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (8 mg, 2.5 equiv), HATU (11 mg, 1.15 equiv), DIEA (13 μL, 3 equiv) were mixed with CH2Cl2 (2 mL) and put on shaker for 1 h at rt. The mixture was diluted with EtOAc (8 mL), washed with 3% aq HCl (2×3 mL), concentrated and purified by preparative HPLC to afford 2-adamantyl 2-((1R,2R)-2-(ethoxycarbonyl)cyclopropanecarbonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (9 mg, 69%).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:8]1[C:3]([C:1]#[C:2][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH:39]4[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]4)=[CH:35][CH:34]=3)[N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ncccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccnc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylpyridin-3-yl)acetate (I120) (0.100 g, 0.571 mmol) in THF (1 mL) and triethylamine (0.199 mL, 1.43 mmol) was added to a mixture of tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I24) (0.217 g, 0.476 mmol), Pd(PPh3)2Cl2 (0.033 g, 0.048 mmol), Cu(I)I (0.014 g, 0.071 mmol) and triphenylphosphine (0.019 g, 0.071 mmol) in dimethylformamide (3 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes then cooled, degassed for 10 minutes and heated under microwave irradiation at 120° C. for a further 20 minutes. The cooled mixture was diluted with ethyl acetate and the resulting solution passed through a plug of Celite, washing with ethyl acetate (250 mL). The volatiles were removed to give a brown solid which was chromatographed (Biotage Isolera: 25 g silica cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I147) (0.061 g, 22%); 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.62 (d, J=1.2 Hz, 1H), 7.72 (dd, J=7.9, 1.3 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.54 (s, 1H), 7.35 (dd, J=7.9, 4.7 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 4.30-4.06 (m) 3.95 (s, 2H), 3.71 (s, 3H), 2.84-2.58 (m, 3H), 2.06-1.98 (m), 1.70-1.66 (m, 2H), 1.69-1.51 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13]Cl)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C.CC(CC)=O>C1C=CC=CC=1>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][O:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[CH:26]([CH3:28])[CH3:27])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Reactant: ClCc1nc(Cc2ccccc2)no1
Solvent: c1ccccc1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(COCc1nc(Cc2ccccc2)no1)c1ccc(Cl)cc1

Procedure:
First, 2.1 grams (0.01 mole) of the intermediate of Example I, 2.3 grams (0.011 mole) of 2-(4-chlorophenyl)3-methyl butyric acid, 1.0 grams (0.01 mole) of triethylamine, and 100 milliliters of methylethylketone were combined and heated under reflux for 2 hours. The mixture was then cooled and poured into 200 milliliters of benzene. The benzene mixture was then washed in turn with 100 milliliters of H2O, 100 milliliters of 5% K2CO3 solution, and 100 milliliters of H2O. The benzene phase was then dried with MgSO4 and evaporated in vacuo to yield 3.0 grams (78% of theory) of the desired product. nD30 1.5210.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[C:5]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:7]3[CH2:8][N:9]=[CH:10][C:11]([CH:12]=1)=[C:6]23.C[I:24].[CH2:25]([Mg]Br)C.C1C2C(=CC=CC=2)C=CN=1>>[I-:24].[CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[C:5]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:7]3[CH2:8][N+:9]([CH3:25])=[CH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: CI
Reactant: COc1cc2c3c(c1OC)CCc1ccccc1C3CN=C2
Reactant: CC[Mg]Br
Solvent: c1ccc2cnccc2c1
Product: COc1cc2c3c(c1OC)CCc1ccccc1C3C[N+](C)=C2
Product: [I-]

Procedure:
By following serially the procedure of step (a) of example 5 and the procedure of example 6, and selecting 5,6-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline (described in example 2) as the starting material of formula II, methyl iodide as the organohalide and ethyl magnesium bromide as the Grignard reagent, (3,12b-trans)-3-ethyl-5,6-dimethoxy-2-methyl-1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta]1,2,3-de]isoquinoline, mp 92°-94° C., was obtained via 5,6-dimethoxy-2-methyl-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]-isoquinolinium iodide, mp 195°-210° C., NMR (DMSO-d6) δ 3.83 (s, 3H), 3.88 (s, 3H), 3.97 (s, 3H), 4.42 (m, 2H), 5.18 (m, 1H), 7.10 (m, 4H), 7.38 (s, 1H), 9.17 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCCCBr
Yield: 101.4 %

Procedure:
According to the method for the synthesis of 206e, 205g (43.0 g, 0.16 mol) was treated with LiBH4 (5.55 g, 0.25 mol) and methanol (7.75 g, 0.24 mol) in CH2Cl2 (200 mL) to give 206g (36.2 g, 98%) as a colorless, viscous oil. 1H NMR (CDCl3): δ 3.41 (t, 2H, J=6.9), 3.30 (br. s, 2H), 1.90-1.84 (m, 3H), 1.42-1.22 (m, 6H), 0.86 (s, 6H). 13C NMR (CDCl3): δ 71.9, 38.6, 35.1, 34.1, 32.9, 29.2, 24.0, 23.2. HRMS (LSIMS, nba): Calcd for C9H18Br (MH+-H2O): 205.0592, found: 205.0563.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li][CH2:9]CCC.CCOCC.[C:18]([O:23][CH2:24][CH3:25])(=[O:22])[CH:19]([CH3:21])[CH3:20].BrCCC=C>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:20][C:19]([CH3:9])([CH2:21][CH2:3][CH:1]=[CH2:2])[C:18]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C(C)C
Reactant: [Li]CCCC
Agent: C=CCCBr
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: C=CCCC(C)(C)C(=O)OCC
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a stirred solution of diisopropylamine (13.38 mL, 94.70 mmol) in anhydrous THF (50 mL), at −70° C. and under nitrogen, was slowly added 2.5 M n-BuLi in ether (36.50 mL, 91.25 mmol). Stirred for 15 minutes, to this reaction solution was then added dropwise ethyl isobutyrate (11.51 mL, 86.09 mmol) in THF (50 mL), stirred for 20 minutes before added dropwise 4-bromo-1-butene (9.79 mL, 96.42 mmol) in HMPA (20 mL). The reaction solution was then stirred to −50° C. in 5 hours, quenched with 1M HCl (10 mL) and water (100 mL), then extracted with (3×125 mL) ether. The combined ether layer was washed with water (4×70 mL), aqueous saturated NaHCO3 (2×70 mL), dried over Na2SO4, filtered and concentrated. The crude product was flash chromatographed on 120 g silica gel 60, eluting with 1-20% EtOAc/Hexane to give the title product as clear oil (11.01 g, 75% yield). LRMS (ESI) m/z 171 [(M+H)+; calcd for C10H19O2: 171].