Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1.[H][H]>[Pd].C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1
Reactant: CCOC(=O)/C=C/C1=CCCOC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1CCCOC1
Yield: 174.1 %

Procedure:
The above was repeated in the exact same fashion with a second batch. Hence a solution of ethyl (2E)-3-(5,6-dihydro-2H-pyran-3-yl)-2-propenoate (2.59 g) and palladium on carbon (147 mg, 10% wet) in ethyl acetate (65 ml) was hydrogenated at atmospheric pressure and room temperature. The hydrogen uptake (˜715 ml) was complete after 15 minutes. The catalyst was filtered through celite and the filtrate concentrated in vacuo. to afford a pale yellow oil which was combined with that of the first batch (5.34 g). This was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-10% cyclohexane:ethyl acetate to afford the title compound as a clear oil (4.61 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:25])=[C:7]([C:9]2[N:14]=[C:13]3[N:15]([CH3:24])[C:16](=[O:23])[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]3=[CH:11][CH:10]=2)[CH:8]=1.[C-:26]#[N:27].[K+]>CN1C(=O)CCC1>[CH3:22][C:19]([CH3:21])([CH3:20])[CH2:18][N:17]1[C:12]2[C:13](=[N:14][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][C:26]#[N:27])[CH:4]=[CH:5][C:6]=3[CH3:25])=[CH:10][CH:11]=2)[N:15]([CH3:24])[C:16]1=[O:23]
Reactant: Cc1ccc(CBr)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(CC#N)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 15 h

Procedure:
To a solution of 82-1 (180 mg, 0.45 mmol) in NMP was added potassium cyanide (32 mg, 0.49 mmol), the vessel was sealed and heated to 120 C. After 15 hours, the reaction was purified by reverse phase chromatography (Sunfire C18, 40-95% CH3CN/0.1% TFA/water). Fractions containing product were partially concentrated, quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give 82-2 as an oil. HRMS (M+H)+: observed=349.1, calculated=349.4.
Reaction SMILES: NC1C=CC=CC=1[S:8][C@@H:9]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:10]([OH:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[OH:20][C@H:10]1[C:11](=[O:12])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:8][C@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1
Reactant: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(=O)Nc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
(2S,3S)-3-(2-Aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-phenylpropionamide (582 mg) is mixed with chlorobenzene (10 ml), and the mixture is refluxed for 25 hours during which thereto is added p-toluenesulfonic acid monohydrate (112 mg) in 8 portions (14 mg×8) at intervals of three hours. The reaction mixture is cooled to room temperature, and concentrated under reduced pressure to remove the chlorobenzene. To the residue is added methanol (5 ml), and the mixture is refluxed for one hour. The mixture is allowed to cool to room temperature, and stirred to crystallization, and then cooled with ice. The precipitated crystals are collected by filtration, washed with chilled methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (243 mg).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:30][S:29]1.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([CH2:54][N:55]2[CH2:57][CH:56]2[CH3:58])[C:51](O)=[O:52])=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([CH2:54][N:55]2[CH2:57][CH:56]2[CH3:58])[C:51]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[S:29][CH2:30][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:52])=[CH:46][CH:45]=1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Reactant: CC1CN1CC(C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC1CN1CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
HBTU (37 mg, 0.097 mmol) was added to a solution of the (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (30 mg, 0.097 mmol) and 2-(4-chlorophenyl)-3-(2-methylaziridin-1-yl)propanoic acid (47 mg, 0.097 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was subject to column chromatography, eluting with EA-DCM/MeOH (20:1-10:1). The product was treated with HCl (4M, 2 mL) afforded 2-(4-chlorophenyl)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-(2-methylaziridin-1-yl)propan-1-one as the HCl salt (1 mg, 2%). LC/MS (APCI+) m/z 458.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:17]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:17][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: CC(O)CNc1ccnc2cc(Cl)ccc12
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(O)CNc1c(Br)cnc2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
A mixture of 12 g of 7-chloro-N-(2-hydroxypropyl)-4-quinolinamine in 112 ml of acetic acid was stirred at room temperature and to it 8 g of bromine was added dropwise over a thirty minute period. After 1.5 hours, a solid formed which was isolated by filtration, dissolved in water and basified with sodium hydroxide, whereupon a solid formed which was collected by filtration. Recrystallization from ethanol yielded 8 g of solid with a melting point of 161°-163° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24]>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(F)cc1N
Product: Cc1ccc(F)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-fluoro-2-methylaniline (36 mg, 0.290 mmol) similar to Example 58 and isolated as a tan solid (4 mg, 6%). 1H NMR (CDCl3): 9.71 (dd, J=0.80, 2.3 Hz, 1H), 8.74–8.71 (m, 1H), 8.68 (dd, J=1.7, 5.0 Hz, 1H), 7.72 (s, 1H), 7.44–7.39 (m, 1H), 7.33–7.28 (m, 2H), 7.02–6.95 (m, 1H), 6.67 (s, 1H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][C:25](=O)[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:31]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+].CCO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][C:25](=[N:33][OH:34])[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:31]=1
Reactant: O=C1CCCc2sc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)nc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1nc2c(s1)CCCC2=NO
Reaction time: 3.5 h

Procedure:
2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-6,7-dihydro-5H-benzothiazol-4-one (24 mg, 0.05 mmol), hydroxylamine hydrochloride (20 mg, 0.3 mmol), sodium acetate (20 mg, 0.3 mmol) and EtOH (2 mL) are combined and stirred 3.5 h. The reaction is diluted with CH2Cl2 and washed with NH4Cl, NaHCO3 and concentrated to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-6,7-dihydro-5H-benzothiazol-4-one oxime. 1H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.34 (d, 1H), 8.20 (s, 1H), 8.07 (d, 1H), 7.59 (dd, 1H), 4.70 (s, 2H), 3.87 (s, 2H), 3.49 (s, 4H), 2.74 (t, 2H), 2.61 (t, 2H), 1.81 (dt, 2H); (Ion Spray) 511 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[N:15]#[C:16][NH2:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[C:8]1([CH:4]2[C:3]3=[N:15][C:16]([NH2:17])=[N:1][N:2]3[CH2:7][CH2:6][O:5]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CN
Reactant: NN1CCOC(c2ccccc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nc2n(n1)CCOC2c1ccccc1
Temperature: 80 °C

Procedure:
4-Amino-2-phenylmorpholin-3-one (175 mg, 910 μmol) and cyanamide (230 mg, 179 μL, 5.46 mmol) were dissolved in ethanol (4 mL). p-Toluenesulfonic acid monohydrate (260 mg, 209 μL, 1.37 mmol) was added and the mixture was heated under reflux at 80° C. for 24 hours. After cooling to room temperature, triethylamine (461 mg, 634 μL, 4.55 mmol) was added and the mixture was heated under reflux at 80° C. for 3 days.
Reaction SMILES: Cl[C:2]1[C:12]([I:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[F:14][C:15]([F:20])([F:19])[CH:16]([OH:18])[CH3:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[I:13][C:12]1[C:2]([O:18][CH:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cnc(Cl)c(I)c1
Reactant: CC(O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OC(C)C(F)(F)F)c(I)c1
Yield: 48.1 %

Procedure:
To a solution of 120 mg (0.39 mmol) of ethyl 6-chloro-5-iodonicotinate (from Step A) and 52 μL (0.58 mmol) of 1,1,1-trifluoro-2-propanol in 5 mL of THF at rt was added 578 μL (0.58 mmol) of sodium bis(trimethylsilyl)amide (1.0 M in THF). After refluxing overnight, the reaction mixture was concentrated. Chromatography on a Biotage 40S cartridge using 1:49 v/v Et2O/hexanes as the eluant gave 73 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.39 (t, J=7.1, 3H), 1.55 (d, J=6.6, 3H), 4.38 (q, J=7.1, 2H), 5.79 (m, 1H), 8.66 (d, J=2.1, 1H), 8.73 (d, J=2.0, 1H).
Reaction SMILES: O.[OH-].[Li+].[OH:4][CH2:5][C@@H:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][CH3:8]>O.C1COCC1>[OH:4][CH2:5][C@@H:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][CH3:8]
Reactant: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
Lithium hydroxide monohydrate (6 mg, 0.14 mmol) in water (1 mL) was added to a solution of methyl 5-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate (25 mg, 0.06 mmol) in THF (1 mL). The mixture was allowed to stir at RT for 16 hours. The THF was removed in vacuo and the resulting solution was partitioned between water (10 mL) and ethyl acetate (25 mL), the ethyl acetate layer was washed with brine (10 mL) and dried (MgSO4). The aqueous layer was then adjusted to pH 7 by addition of 1M hydrochloric acid and extracted with ethyl acetate (25 mL). The ethyl acetate layer was washed with brine (10 mL) and dried (MgSO4). The ethyl acetate extracts were combined and evaporated to give the required product (12 mg). m/z 428.44 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]#[CH:15]>CO>[CH2:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:14]#[CH:13]
Reactant: C1COCCN1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCN1CCOCC1
Reaction time: 4 h
Yield: 69.6 %

Procedure:
Morpholine (100 ml, 1.148 mol) was dissolved in MeOH (1 L) and cooled in ice under nitrogen, then potassium carbonate (120 g, 0.63 mol) and propargyl bromide (124 mL, 1.148 mol) were added while stirring in ice. Stirring without cooling was continued for 4 h. The white suspension was filtered through paper and the solids were washed with MeOH (100 ml) and the MeOH was carefully evaporated. The white precipitate was suspended in DCM (400 ml), filtered through paper, and carefully evaporated. Finally the oil was distilled at 60° C./16 mbar. One obtained 100 g (70%) of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9]/[C:8](=[CH:12]\N(C)C)/[C:7]1=O)[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]([NH2:43])=[NH:42])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[C:7]2[N:43]=[C:41]([NH:40][C:30]3[CH:31]=[CH:32][C:33]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:28]([O:27][CH3:26])[CH:29]=3)[N:42]=[CH:12][C:8]=2[CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)CC1CCC/C(=C\N(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)CC1CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from crude {3-[1-dimethylamino-meth-(E)-ylidene]-2-oxo-cyclohexyl}-acetic acid ethyl ester (108 mg, 0.33 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (111 mg, 0.30 mmol) using in analogous manner the procedure described in example 45b). Obtained as yellow crystals (83 mg, 66%). MS ISP (m/e): 422.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.60 (s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.27 (d, 1H), 7.20 (d, 1H), 7.02 (s, 1H), 4.06 (q, 2H), 3.79 (s, 3H), 3.10 (m, 2H), 2.60-2.70 (m, 3H), 2.14 (s, 3H), 2.02 (m, 1H), 1.86 (m, 1H), 1.65 (m, 2H), 1.15 (t, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:22])[CH2:3]1.[CH2:23](OC([O-])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CNC1C=CC=CC=1.C=O>>[CH3:1][C@@H:2]1[C@@:19]2([CH3:20])[C:6]([C:7](=[CH2:23])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:22])[CH2:3]1
Reactant: CCOC([O-])OCC
Reactant: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CNc1ccccc1
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)C[C@@H]2C
Yield: 75 %

Procedure:
With a procedure similar to the one described in Example 1, 3 g of 1α-methylandrost-4-ene-3,17-dione, 3 ml of diethylorthoformate, 80 mg of p-toluenesulphonic acid, 1.1 ml of N-methylaniline and 1,2 ml of a 40% formic aldehyde aqueous solution give 2.34 g (75% yield) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:18]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:30]2[CH2:29][CH2:28][CH:27]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[N:19]3)[CH2:32][CH2:31]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)nnn2C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C(CCN2CCC(n3nnc4ccccc43)CC2)c2ccccc2)cc1
Yield: 41 %

Procedure:
The procedure shown in Example 2 was followed except that 3,3-diphenylpropyl bromide (570 mg, 2.1 mmol), 4-benzotriazol-1-yl-piperidine hydrochloride (250 mg, 1.05 mmol), potassium carbonate (580 mg, 4.2 mmol) and DMF (5 ml) were used to give the title compound as a gum (170 mg, 0.43 mmol); NMR: 2.2 (m, 9H), 3.0 (m, 2H), 4.0 (m, 2H), 4.8 (m, 1H), 7.1 (m, 2H), 7.3 (m, 9H), 7.5 (t, 1H), 7.8 (d, 1H) and 8.05 (d, 1H); MS: 397.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:9][C:8]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH:32]=O)=[CH:27][CH:26]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:41].[CH3:42][NH:43][CH3:44].C1COCC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])=[CH:9][C:8]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH2:32][N:43]([CH3:44])[CH3:42])=[CH:27][CH:26]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:41]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)Cc1ccc2c(c1)cc(-c1cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 82.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (74.9 mg, 0.125 mmol) was dissolved in acetonitrile (2.5 mL), and the solution was treated with 2.0 mol/L dimethylamine-THF solution (0.63 mL, 1.25 mmol), acetic acid (0.072 mL, 1.25 mmol) and sodium triacetoxyborohydride (76.5 mg, 0.375 mmol), followed by purification by flash column chromatography (chloroform/methanol=19/1, 4/1) to obtain 4-chloro-5-[3-(tert-butyldimethylsiloxy)propyloxy]-7-[1-(tert-butoxycarbonyl)-5-(dimethylaminomethyl)indol-2-yl]isoindolinone (65.0 mg, yield 83%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C:20]#[CH:21]>O1CCCC1>[C:24]([O:23][C:19](=[O:22])[C:20]#[C:21][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:27])([CH3:26])[CH3:25]
Reactant: C#CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C#CC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
To the mixture of methyl 3-iodobenzoate (157 mg, 0.60 mmol), potassium carbonate (166 mg, 1.20 mmol), cupper(I) iodide (14 mg, 0.07 mmol) and PdCl2(Ph3P)2 (21 mg, 0.03 mmol) in tetrahydrofuran (2 mL) was added tert-butyl propiolate (330 μL, 2.40 mmol) at room temperature. After stirred for 20 h at 60° C., the mixture was evaporated to dryness. The residue was chromatographed on a silica gel (EtOAc:hexanes=0:1˜1:10) to give the title compound 9-1 (155 mg, 99% yield) as a light brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:70]1[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=1[C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])=[N:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(Br)cn2)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(-c3ccccn3)cn2)cc1F
Temperature: 80 °C
Yield: 18.5 %

Procedure:
A solution of 0.68 g (1 mmol) (2S,4R)-5-Bromo-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, 0.28 g (1.1 mmol) bis(pinacolato)diboron, 0.29 g (3 mmol, dried 2 h at 100° C., 0.1 Torr) potassium acetate and 0.024 g (0.03 mmol) PdCl2(dppf) in 12 ml DMF were stirred for 4.5 h at 80° C. The reaction was cooled, treated with 0.195 ml (2 mmol) 2-bromopyridine, 0.024 g (0.03 mmol) PdCl2(dppf) and 2.5 ml aqueous 2 M Na2CO3 solution and heated for 16 h at 80° C. The reaction evaporated (60° C./0.1 torr) and partitioned between water/Et2O (3×). The organic phases were washed with aqueous 10% NaCl and dried over Na2SO4. Purification by flash-chromatography on silica gel (toluene/EtOAc 97.5:2.5) gave 0.125 g (2S,4R)-5-Pyridin-2-yl-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 675 (MH+). TFA/triisopropylsilane deprotection (see General method for S-deprotection, Method D) gave (3R,5S)-1-(5-Pyridin-2-yl-pyrimidin-2-yl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol; compound with trifluoro-acetic acid, MS: 433 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26](O)=[O:27])[C:20](=[O:29])[CH:19]=[CH:18]2)#[N:14]>>[Cl:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][N:21]2[C:22]3[C:17](=[CH:16][C:15]([C:13]#[N:14])=[CH:24][CH:23]=3)[CH:18]=[CH:19][C:20]2=[O:29])[S:5][CH:6]=1
Reactant: N#Cc1ccc2c(ccc(=O)n2CC(=O)O)c1
Reactant: Nc1scc(Cl)c1-c1nc[nH]n1
Product: N#Cc1ccc2c(ccc(=O)n2CC(=O)Nc2scc(Cl)c2-c2nc[nH]n2)c1

Procedure:
The title compound was prepared from 4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (215 mg, 1.07 mmol) and 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (325 mg, 1.42 mmol) using protocol A. HPLC purification gave N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide. Method [7] Retention time 3.83 min by HPLC (M+=411 and 413). 1H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 2H), 8.13 (d, J=9.9 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.17 (s, 1H), 6.86 (d, J=9.9 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]>C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][S:32]([CH2:28][CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCS(=O)(=O)NCCOc1cccc2c1CC(N(CCC)CCC)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 g (8.6 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene and 2.4 g (17.2 mmol) of potassium carbonate were initially introduced into 40 ml of toluene. 1.5 g (9.5 mmol) of butanesulphonyl chloride were added dropwise, and the mixture was then stirred for a further 2 h at room temperature. The mixture was then filtered and evaporated in a rotary evaporator. After chromatography on silica gel 60, 40-63 μm, using diisopropyl ether/ethanol, 3:2, the product was recrystallized from petroleum ether.