Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([Cl:14])[C:5]2[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:22][C@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C>[Cl:14][C:4]1[C:5]2[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[CH2:8][C:6]=2[N:7]=[C:2]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@@H:23]2[CH3:22])[N:3]=1
Reactant: CC1c2c(Cl)nc(Cl)nc2CS1(=O)=O
Reactant: C[C@H]1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1c2c(Cl)nc(N3CCOC[C@@H]3C)nc2CS1(=O)=O
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (150.0 mg, 0.5926 mmol) and Et3N (119.9 mg, 1.2 mmol) in DMF (2.0 mL) was added (S)-3-methylmorpholine (59.9 mg, 0.6 mmol) dropwise. The reaction mixture stirred overnight, then quenched by addition of H2O and the resulting mixture extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20:1-2/1) to provide 4-chloro-5-methyl-2-[(3S)-3-methylmorpholin-4-yl]-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (B) as a light yellow solid (50 mg, 13.5%). Further elution then provides 2-chloro-5-methyl-4-[(3S)-3-methylmorpholin-4-yl]-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (A) as an off-white soild (100 mg, 27%),
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[F:8][C:7]1[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Cl
Reactant: C#CCCn1nc2ccccc2n1
Product: Fc1cccnc1C#CCCn1nc2ccccc2n1
Yield: 27586.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-chloro-3-fluoropyridine (42 mg, 0.32 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (50 mg, 0.29 mmol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 21 mg (80 mmol, 27%) of 2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([CH3:15])=[CH2:14]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C=C(C)Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-cyanophenylboronic acid (10.0 g, 68.05 mmol) dissolved in DME (340 mL) is added 2-bromopropene (6.86 g, 56.7 mmol), and sodium carbonate (62.3 mL of a 2 M solution in water, 124.7 mmol). The reaction mixture is degassed for 20 min with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (2.54 g, 2.2 mmol) is added, the reaction mixture degassed for 10 min, and heated at reflux overnight. The reaction mixture is cooled to room temperature and then partitioned between hexanes and water. The aqueous layer is extracted with hexanes (3×75 mL). The combined organic layers are washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (9:1 hexanes/ethyl acetate) provides the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.96 (m, 1H), 7.85 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.56 (m, 1H) 5.58 (s, 1H), 5.23 (m, 1H), 2.13 (s, 3H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)Cl
Reactant: COc1ccc(OCCO)cc1
Product: COc1ccc(OCCOS(N)(=O)=O)cc1
Yield: 54 %

Procedure:
The title compound was prepared by procedures of Example 28 from sulfamoyl chloride and 2-(4-methoxyphenoxy)ethanol in 54% yield as an off-white solid, mp 84°-87° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:42]([N:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]([CH2:58][CH2:59][NH2:60])=[CH:50]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([N:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]([CH2:58][CH2:59][NH:60][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=2)[C:30]([OH:32])=[O:31])=[CH:50]1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: NCCc1cn(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCc1cn(Cc2ccccc2)c2ccccc12
Yield: 48.4 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (73 mg, 0.13 mmol) and 2-(1-benzyl-1H-indol-3-yl)ethylamine hydrochloride (45 mg, 0.16 mmol) according to Method C to give the title compound (48 mg). 1H-NMR (400 MHz, CD3OD) d 7.56 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.28 (s, 2H), 4.69 (s, 2H), 4.48 (m, 1H), 4.22 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 3.52 (m, 1H), 3.38 (m, 1H), 2.98 (m, 2H), 2.86 (m, 3H), 2.72 (dd, J=9.3 Hz, J=13.8 Hz, 1H), 1.33 (s, 9H); HRMS m/z 762.3292 (calc. of monoisotopic mass for C43H46N4O9 gives 762.3265).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](N3C=NC=N3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([OH:36])[CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([O:36][C:28]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C)n2nc(-c3ccc(Br)cc3)nc(-n3cncn3)c12
Reactant: COc1cc(O)cc(OC)c1OC
Product: COc1cc(Oc2nc(-c3ccc(Br)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
Preparation analogously to Example 22 from Example 50A (50 mg, 0.14 mmol) and 3,4,5-trimethoxyphenol (50 mg, 0.29 mmol).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:12][S:13]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCC2(CC1)OCCO2
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,4-Dioxaspiro[4.5]decan-8-ol (0.40 g, 0.0025 mol) was dissolved in chloroform (10.0 mL) and the resulting mixture was cooled at 0° C. To the mixture was added TEA (0.49 mL, 0.0035 mol) and methanesulfonyl chloride (0.23 mL, 0.0030 mol) and this mixture was stirred at 0° C. for 2 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([N:12]1[CH2:16][C:15]2=[CH:17][C:18]3[C:19]([O:25][CH3:26])=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][CH:14]2[C:13]1=[O:27])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>O1CCCC1.O>[CH3:26][O:25][C:19]1[C:18]2[CH2:17][C:15]3[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[C:3]([OH:28])=[O:2])[C:13](=[O:27])[C:14]=3[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC2=Cc3c(OC)cccc3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Yield: 94.6 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid methyl ester (1.2 g, 3.13 mmol) and lithium hydroxide monohydrate (0.17 g, 4.04 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (20 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (1.1 g, 95.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([NH2:27])=[N:24][C:23]=2[CH:28]=1)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([NH:27][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:24][C:23]=2[CH:28]=1)[CH3:17]
Reactant: CCOc1ccc2sc(N)nc2c1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CCOc1ccc2sc(NC3c4cc(C#N)ccc4OC(C)(C)C3O)nc2c1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-ethoxy-benzothiazol-2-ylamine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:4]([O:9][CH:16]([F:21])[F:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(OC)c1c(O)ccc(F)c1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1c(OC(F)F)ccc(F)c1Cl
Temperature: 90 °C
Yield: 62.8 %

Procedure:
In a single neck flask, 3-chloro-2-dimethoxymethyl-4-fluorophenol (22 g, 100 mmol), sodium chlorodifluoroactate (30.3 g, 200 mmol) and potassium carbonate (27.5 g, 200 mmol) were taken up in DMF (145 mL) under nitrogen atmosphere and heated at 90° C. for 16 h. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2×200 mL, 100 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as an eluent to give 17 g (63% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): δ=7.11-7.13 (m, 2H), 6.45 (t, J=75 Hz, 1H), 5.70 (s, 1H), 3.46 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([C:35]#[C:36][Si](C)(C)C)=[N:23][N:24]4[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:35]([C:22]1[C:21]2[C:25](=[CH:26][C:18]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[O:10])=[CH:17][CH:16]=3)=[CH:19][CH:20]=2)[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[N:23]=1)#[CH:36]
Reactant: C[Si](C)(C)C#Cc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)ccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of Example 21B (660 mg) in 50 ml methanol was treated with excess K2CO3, stirred at 50° C. for 1 hour, then concentrated to ca. 2 mL and partitioned between ethyl acetate and brine. The aqueous layer was back extracted with ethyl acetate, the combined organic extracts were dried (MgSO4) and concentrated and the residue was purified via silica gel chromatography eluting with 0 to 0.75% methanol in CH2Cl2. to afford the title compound.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24]>>[C:1]1([S:7][CH:8]([N:18]2[C:22](=[O:23])[C:21]3=[CH:6][CH:1]=[CH:2][CH:3]=[C:20]3[C:19]2=[O:24])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CSc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(C(Sc2ccccc2)N2C(=O)c3ccccc3C2=O)cc1

Procedure:
The reaction of Example 1 is repeated with 0.13 m of p-methoxybenzyl phenyl sulfide and N-bromosuccinimide to give N-[α-(phenylthio)-p-methoxybenzyl]-phthalimide and, then, the N-(α-chloro-p-methoxybenzyl)phthalimide using sulfuryl chloride. The p-methyl and p-nitro congeners are prepared similarly.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:27])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[O:1]([CH2:8][CH:9]([OH:27])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared by catalytic reduction of 1-phenoxy-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-butanol with hydrogen over palladium on carbon.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH3:10]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH3:10])=[O:4]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)C(=O)OC

Procedure:
2,2-Dimethyl-4-pentenoic acid (15 g, 0.117 mol) was mixed with 70 mL anhydrous methanol and 50 mL toluene. Concentrated sulfuric acid (0.1 mL) was added. The solution was refluxed for 24 h. Solvents were then removed. The crude product was distilled under reduced pressure to gave 6 g pure product. 1H NMR (CDCl3): δ 1.28 (s, 6H, —CMe2-); 2.37 (d, 2H, CH2═CHCH2—); 3.77 (s, 3H, —CO2Me); 5.15 (m, 2H, CH2═CH—); 5.84 (m, 1H, CH2═CH—).
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:23])[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[Cl-].[NH4+]>C1COCC1>[O:23]=[C:7]([CH3:1])[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1
Reactant: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methylmagnesium bromide (1 M THF solution, 30 mL) was added dropwise to a solution of tert-butyl 4-{3-[methoxy(methyl)amino]-3-oxopropyl}piperidine-1-carboxylate (4.5 g) in THF (50 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.70 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[C:8]([CH3:23])[C:6]=3[N:7]=2)=[CH:39][N:40]=1
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 14.7 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 50 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 10 mg of 201. MS (Q1) 499.3 (M)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: COc1ccccc1Br
Product: COc1ccccc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromoanisole. Light yellow solid. MS (ESI): 421.0 (MH+)
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:50][CH:49]=1)[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25]>>[C:55]([O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][C@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:53][CH:52]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 85 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]5)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=O)=O.[C-:33]#[N:34].[Na+]>CS(C)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:32]=[C:28]1[NH:29][CH2:30][CH2:31][N:26]([CH:23]2[CH2:24][CH2:25][CH:20]([O:19][C:10]3[C:9]4[C:8]5[C@@H:7]([CH2:6][C:33]#[N:34])[CH2:18][CH2:17][C:16]=5[S:15][C:14]=4[N:13]=[CH:12][N:11]=3)[CH2:21][CH2:22]2)[CH2:27]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of [(3S)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (450 mg, 0.94 mmol, 1.00 equiv) in DMSO (10 mL) was added NaCN (276 mg, 5.63 mmol, 6.00 equiv) and DMAP (11 mg, 0.094 mmol, 0.10 equiv) at room temperature. The resulting solution was stirred for 2 h at 80° C. After cooling to r.t, the resulting solution was diluted with DCM (100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with DCM/MeOH (10:1) to afford 330 mg (86%) of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetonitrile as a yellow solid.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3].[CH:10]([OH:13])([CH3:12])[CH3:11]>O1CCOCC1>[CH:10]([O:13][C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3])([CH3:12])[CH3:11]
Reactant: O=C(Cl)N1CCNC1=O
Reactant: CC(C)O
Solvent: C1COCCO1
Product: CC(C)OC(=O)N1CCNC1=O

Procedure:
14.9 parts by weight of N-chlorocarbonylimidazolid-2-one in 100 parts by volume of i-propanol and 100 parts by volume of dioxane were warmed to 50° C for 3 hours. After stripping off the solvent, the residue was recrystallized from acetone.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]2[CH2:24][C:25](=[O:28])[CH2:26][CH2:27][C@@H:10]2[CH2:9]1)=[O:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[C@H:13]([CH2:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:12][N:11]3[CH2:24][C@@H:25]([OH:28])[CH2:26][CH2:27][C@@H:10]3[CH2:9]2)=[O:7])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=1
Reactant: O=C1CC[C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)CN2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](O)CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a suspension of (3R,9aR)-2-[3,5-bis(trifluoromethyl)benzoyl]-3-(1H-indol-3-ylmethyl)-octahydro-2H-pyrido[1,2-a]pyrazin-7-one (5.6 g) in acetic acid (75 mL) was added sodium triacetoxyborohydride (6.78 g). The resulting mixture was stirred for one hour at room temperature then poured in water and basified with 2M sodium hydroxide (aq.). The formed precipitate was collected by filtration, washed with water, suspended in toluene and concentrated in vacuo to afford 3,5-bis(trifluoromethyl) phenyl-[(3R,7S,9aR)-7-hydroxy-3-(1H-indol-3-ylmethyl)-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (5.7 g). Rf 0.35 (CH2Cl2/MeOH 9:1) (compound 12).