Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=O)[CH:17]=3)[CH:12]=[N:11]2)=[CH:7][CH:6]=1.[CH2:23]1COCC1>C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br-]>[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[CH2:23])[CH:17]=3)[CH:12]=[N:11]2)=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: COc1ccc(Cn2ncc3ccc(C=O)cc32)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc2cnn(Cc3ccc(OC)cc3)c2c1
Temperature: 0 °C
Yield: 61 %

Procedure:
An oven-dried flask under N2 (g) was charged with NaH (60% wt) (592 mg, 14.8 mmol) and THF (30 mL) and the suspension cooled to 0° C. CH3PPh3Br (5.29 g, 14.8 mmol) was added and stirred for 30 min at which time 1-(4-methoxybenzyl)-1H-indazole-6-carbaldehyde (1.97 g, 7.40 mmol) was added and the reaction was allowed to slowly warm to room temperature. After 2.5 h quenched with NH4Cl and extracted with Et2O. The organic layers were washed with brine (2×) and dried over MgSO4. The solvent was removed and the residue purified using Biotage Isolera (silica gel, 10-20% EtOAc in hexane) to give the title compound as a white solid (1.20 g, 61%); 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.30-7.26 (m, 2H), 7.16 (d, J=8.3 Hz, 2H), 6.84-6.76 (m, 3H), 5.80 (d, J=17.5 Hz, 1H), 5.53 (s, 2H), 5.30 (d, J=10.9 Hz, 1H), 3.76 (s, 3H); MS ESI 264.9 [M+H]+, calcd for [C17H16N2O+H]+ 265.1.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.[F:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:33]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:26])[CH:34]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)c(F)c3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and 2,4-difluorobenzonitrile using procedures analogous to those for Example 14. Analytic LCMS (M+H)+: m/z=444.4.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@H:14]([CH2:18][O:19][CH3:20])[C:15]([NH2:17])=[O:16].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:13][C@H:14]([CH2:18][O:19][CH3:20])[C:15]([NH2:17])=[O:16])[CH:9]=1
Reactant: COC[C@@H](N)C(N)=O
Reactant: N#Cc1cc(F)c(F)cc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COC[C@@H](Nc1cc(Br)c(C#N)cc1F)C(N)=O
Yield: 21.4 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (168 mg, 0.770 mmol), (R)-2-amino-3-methoxypropanamide hydrochloride (120 mg, 0.776 mmol) and DIEA (0.500 mL, 2.87 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, which was eluted with 0-70% EtOAc in hexane to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-methoxypropanamide (52 mg).
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4]CC1.[CH2:29]([Mg]Br)C(C)C>>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:26])([F:27])[F:25])[CH:14]=[CH:15][C:7]=2[CH:6]([CH2:1][CH:5]([CH3:4])[CH3:29])[O:10]1
Reactant: CC(C)C[Mg]Br
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Product: CC(C)CC1OB(O)c2cc(NC(=O)c3ccccc3C(F)(F)F)ccc21

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with isobutyl magnesium bromide replacing cyclopentyl magnesium bromide. Data: LCMS (M/Z): 378 (M+H); 1H NMR (DMSO-d6) δ: 10.53 (s, 1H), 9.13 (s, 1H), 8.06 (d, J=1.9 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.73-7.79 (m, 1H), 7.65-7.71 (m, 2H), 7.62 (dd, J=8.2, 2.0 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 5.10 (dd, J=9.8, 3.0 Hz, 1H), 1.81-1.92 (m, 1H), 1.65 (ddd, J=13.9, 9.0, 3.1 Hz, 1H), 1.27 (ddd, J=14.1, 9.7, 4.6 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([N:16]=[C:17]=[S:18])(=O)C1C=CC=CC=1>C(O)C>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:17]([NH2:16])=[S:18]
Reactant: Nc1cnccn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCO
Product: NC(=S)Nc1cnccn1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Aminopyrazine (2 g, 21.03 mmol) is dissolved in ethanol (20 ml) and benzoylisothiocyanate (2.82 ml) is added dropwise. The mixture is heated to 80° C. with stirring for 10 minutes then allowed to cool to room temperature. The solvent is removed in vacuo and the resulting solid dissolved in 1M sodium hydroxide (30 ml) and heated under reflux for 1 hour. The resultant suspension is filtered and the solid washed with water and a little cold methanol. The solid is dried in vacuo to yield the title compound, m.p. 239–239.5° C., m.s. (AP+) 138 (M+—NH3). Other thioureas of formula III are prepared in an analogous manner from the appropriate starting amine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([F:10])[CH:3]=1.S(Cl)([Cl:13])=O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([F:10])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)cc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Fc1cc(Cl)ccc1CCl

Procedure:
Then, 16.5 g of 4-chloro-2-fluorobenzylalcohol was dissolved in 150 ml of tetrahydrofuran and 1 ml of pyridine, to which 10 ml of thionyl chloride was added dropwise at 5° C., and the mixture was stirred for 2⅚ hours. After completion of the reaction, the reaction mixture was concentrated, and the precipitated crystals were collected by filtration. The filtrate was subjected to silica gel column chromatography, which afforded 18.5 g of 4-chloro-2-fluorobenzyl chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([NH2:17])=[C:5]([C:15]#[N:16])[CH:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[C:8]#[N:9].[OH-].[NH4+]>C(O)C>[NH2:1][C:2]1[NH:17][C:4](=[S:3])[C:5]([C:15]#[N:16])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#CC1=C(N)SC(N)=C(C#N)C1c1ccco1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccco1
Yield: 55.3 %

Procedure:
To a stirred solution of 310 mg (1.27 mmol) 2,6-diamino-4-furan-2-yl-4H-thiopyran-3,5-dicarbonitrile in 20 ml ethanol was added 7.5 ml 25% ammonium hydroxide solution and the mixture was heated at reflux for 2 hours. The reaction mixture was then concentrated in vacuo and the residue triturated in ether to afford 170 mg (55%) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile as a dark red crystalline solid. EI-MS m/e (%): 242 (M+, 100).
Reaction SMILES: N(CCC1C=CC(F)=CC=1)=[N+]=[N-].[CH2:13]([N:20]=[N+:21]=[N-:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([C:38]#[CH:39])=[N:35][C:34]=1[CH3:40])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([C:38]2[N:22]=[N:21][N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:39]=2)=[N:35][C:34]=1[CH3:40])=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Agent: [N-]=[N+]=NCCc1ccc(F)cc1
Product: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 40 %

Procedure:
Following the procedure as described in Example 1, making variations as necessary to replace 1-(2-azidoethyl)-4-fluorobenzene with benzylazide to react with N-benzyl-2-ethynyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 40% yield: mp 108-109° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.49-7.18 (m, 10H), 6.35 (t, J=5.3 Hz, 1H), 5.51 (s, 2H), 4.56 (d, J=5.3 Hz, 2H), 2.65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 157.9, 156.6, 142.9, 137.8, 133.7, 129.3, 129.1, 128.8, 128.5, 127.8, 127.7, 124.8, 121.5, 54.6, 44.2, 17.2; MS (ES+) m/z 390.3 (M+1).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].O[Li].O>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][C@@H:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H]1C[C@H](Nc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](Nc2cccc(Cl)c2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of the (2S,4S)-4-(3-chloro-phenylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (200 mg, 0.58 mmol) in THF (2 ml) was added a solution of LiOH.H2O (73 mg 1.74 mmol), and the reaction stirred at room temperature overnight. The solvent was concentrated in vacuo and the residual aqueous solution washed with DCM (2 ml). The aqueous was then adjusted to pH 5 with saturated aqueous citric acid and re-extracted with DCM (2×10 ml). These combined extracts were dried over MgSO4 and evaporated to give the title compound as a white foam (168 mg, 88%)
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:12]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH2:15])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: Nc1ccccc1
Product: Nc1ccccc1C1(c2ccccc2N)c2ccccc2-c2ccccc21

Procedure:
More specifically, a symmetrical compound can be synthesized by the following method: A mixture containing a fluorenone and an aniline is refluxed in the presence of an acid catalyst to produce an intermediate 9,9-bis(aminophenyl)fluorene. The intermediate is subsequently reacted with aryl halides (Ar—X and Ar′—X, stepwise) in the presence of a catalyst such as palladium to obtain the desired symmetrical product. An asymmetrical compound, on the other hand, can be synthesized as follows: A reaction mixture containing a fluorenone and two different anilines (e.g., an aniline and a 2-fluoroaniline as shown in the above scheme) is refluxed in the presence an acid catalyst to produce a mixture including an asymmetric fluorene intermediate. The asymmetric fluorene intermediate is then reacted with aryl halides (Ar—X and Ar′—X, stepwise) in the presence of a catalyst such as palladium to produce the desired asymmetrical product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17]2[C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:20](=[O:27])[NH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[H-].[Na+]>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17]2[C@H:26]3[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:20](=[O:27])[N:19]([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reaction time: 5 h

Procedure:
15 g of 1,4-dibromobutane was added to a mixture of 5.0 g of compound 1 and 1.0 g of sodium hydride in dimethylformamide. After stirring the resulting mixture for 5 hours, the solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane). M.p. colourless oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[S:16][CH3:17])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[S:16][CH3:17])[C:10]([Cl:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ccc(C(=O)O)cc1OC1CCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)Cl)cc1OC1CCCC1

Procedure:
3-Cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) is dissolved in toluene (20 mL) and heated at 80° C. for 1 hour 30 minutes in the presence of thionyl chloride (5 mL). The reaction mixture is concentrated to give 3-cyclopentyloxy-4-(methylthio)benzoyl chloride (0.76 g), in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[O-].[Na+].[I-].[K+].Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>CO.C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(Oc1cc(Cl)cc(Cl)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 4.08 g of 3,5-dichlorophenol, 1.188 g of sodium methoxide, and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is maintained at reflux overnight and then added to 100 ml of water. The product is then extracted with ether, and the ether is washed with 5% sodium hydroxide, water, brine, and dried (MgSO4). Evaporation of the solvent yields an oil which is chromatographed on 100 g of silica gel (benzene, 400 ml) to yield a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][S:22]([C:15]1[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCCO)c1c(Cl)cc(Cl)cc1Cl

Procedure:
To 40 parts of tetrahydrofuran are added 1.4 parts of 3-amino-1-propanol and 1.8 parts of triethylamine. Into this solution, 10 parts of tetrahydrofuran containing 5 parts of 2,4,6-trichlorobenzenesulfonyl chloride is dropped with stirring. After the dropping, the resultant mixture is stirred for 1 hour. After completion of the reaction, the salt is removed by filtration, and the filtrate is freed from the solvent. The resulting oily substance is charged with water and then allowed to stand to form a solid. This solid is recrystallized from toluene to obtain 3.8 parts of N-3-hydroxypropyl-2,4,6-trichlorobenzenesulfonamide, m.p. 104.5°-106.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:28])[CH:17]([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)C>>[Cl:26][C:21]1[CH:20]=[C:19]([CH2:18][CH:17]([CH3:27])[C:16]([OH:28])=[O:15])[CH:24]=[CH:23][C:22]=1[O:25][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Reactant: CCCSc1ncccc1CCl
Product: CCCSc1ncccc1COc1ccc(CC(C)C(=O)O)cc1Cl
Yield: 70.2 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (32 mg, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (42 mg, 0.17 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (40 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:44])[O:42][CH3:43]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:41](=[O:44])[O:42][CH3:43])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)Cl
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NC(=O)OC)cc1

Procedure:
To a mixture of 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzenesulfonamide (0.2 g), triethylamine (0.11 ml), 4-dimethylaminopyridine (23 mg) and methylene chloride (2.0 ml) was added methyl chlorocarbonate (35 μl) at room temperature with stirring, and the mixture was stirred at the same temperature for 1 hr. After the completion of the reaction, the reaction mixture was washed with 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=3/1-1/1), crystallized from hexane/ethyl acetate=3/2 to give the title compound (0.15 g) as colorless crystals. 1H NMR (CDCl3) δ: 0.48 (3H, t, J=6.9 Hz), 1.69 (2H, q, J=6.9 Hz), 3.68 (3H, s), 5.38 (2H, s), 7.23-7.32 (2H, m), 7.41 (2H, d, J=8.7 Hz), 7.44-7.53 (5H, m), 7.69 (1H, dd, J=2.1, 8.4 Hz) 7.98 (2H, d, J=8.7 Hz), 8.40 (1H, d, J=8.4 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:13])[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-caboxylate (1.5 g, 6.5 mmol) and potassium carbonate (0.99 g, 7.15 mmol) in DMF (25 mL) was stirred at room temperature for 15 min followed by the addition of methyl iodide (0.42 mL, 6.83 mmol). The resulting suspension was stirred at room temperature for 17 h. The mixture was partitioned between ethylacetate and water. The organic phase was separated and the aqueous phase was extracted with ethylacetate. The organic extracts were combined, washed with brine, dried over MgSO4 and concentrated to afford the title compound as a light yellow solid. MS m/z: 246(M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.I[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]#[CH:25].C([O-])([O-])=O.[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:23]([O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=1)[C:24]#[CH:25]
Reactant: C#CCOCCOCCI
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOCCOCCOc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To tert-butyl 4-hydroxyphenylcarbamate (1.675 g, 8.01 mmol) in DMF (53.4 mL) was added 3-(2-(2-iodoethoxy)ethoxy)prop-1-yne (2.034 g, 8.01 mmol) and K2CO3 (3.32 g, 24.02 mmol). The mixture was stirred at 60° C. for 4 hours followed by the addition of saturated sodium bicarbonate. The mixture was then extracted with ethyl acetate twice, dried over MgSO4, filtered, and then concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% ethyl acetate/heptane) giving tert-butyl 4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)-phenylcarbamate (I-7a: 1.91 g, 71%) as a colorless oil. LC-MS (M-tBu+1) 280.1, t=1.31 minute.
Reaction SMILES: ClCCl.C(N(CC)CC)C.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[CH2:24][CH2:23]1)[C:17](=[O:40])[CH2:16][CH2:15]2.[C:41](OC(=O)C)(=[O:43])[CH3:42]>O>[C:41]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:39])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[CH2:26][CH2:27]1)[C:17](=[O:40])[CH2:16][CH2:15]2)(=[O:43])[CH3:42]
Reactant: COc1ccc(C(=O)N2CCC(N3C(=O)CCc4cc(N)ccc43)CC2)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)N2CCC(N3C(=O)CCc4cc(NC(C)=O)ccc43)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dichloromethane (10 ml) and triethylamine (0.15 ml) are added to 6-amino-1-[1-(2,4-dimethoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.3 g). Acetic anhydride (0.2 ml) is added thereto and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and extracted with dichloromethane. After concentration, the residue is purified by silica gel column chromatography (solvent; chloroform:methanol=20:1) and further recrystallized from ethanol to give 6-acetylamino-1-[1-(2,4-dimethoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.25 g) as white powder, m.p. 271°-272° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:19]=2)[CH:17]=O)([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:24]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([NH:22][CH2:17][C:16]2[CH:19]=[C:12]([C:9]([CH3:11])([CH3:10])[C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:13]=[CH:14][C:15]=2[O:20][CH3:21])[C@@H:24]1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1C=O
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 68 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C=O.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>O.CCOC(C)=O>[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].[NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC2NCCCC2C1
Agent: C#C[Si](C)(C)C
Agent: C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C1CC[C@@H]2NCCC[C@@H]2C1
Yield: 26 %

Procedure:
A solution of the cis/trans mixture of decahydroquinoline diastereomers (1.20 g, 3.48 mmol), formaldehyde (1.1 mL, 13.9 mmol) as a 37 wt % solution in H2O, trimethylsilyl acetylene (963 μL, 6.95 mmol), and AuBr3 (455 mg, 1.04 mmol) in H2O (2.0 mL) was heated at 75° C. overnight. LC/MS of an aliquot showed the reaction had not gone to completion. The reaction mixture was charged with a second portion of formaldehyde (1.1 mL, 13.9 mmol) as a 37 wt % solution in H2O and trimethylsilyl acetylene (963 μL, 6.95 mmol) and heated at 75° C. for an additional 72 hr. The reaction mixture was diluted with EtOAc and filtered through a Celite pad, washing with EtOAc (25 mL). The solution was concentrated and purified by chromatography, eluting with 0-20% EtOAc/hexanes to give 413 mg (26%) of the cis-decahydroquinoline trimethylsilyl acetylene as a colorless oil confirmed by MS (ESI+): cal'd [M+H]+ 466.6, exp. 466.1.