Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>>[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH:29][C:15](=[O:17])[C:14]([N:11]3[CH2:10][CH2:9][CH:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)=[O:18])[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: Nc1ccc2nc(N)sc2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Product: Nc1nc2ccc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)cc2s1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 2,6-diamino-benzthiazole [Arch. Pharm., 13, 48. (1935)] according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 203° C. (isopropanol)
Reaction SMILES: N#N.C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][O:31][C:30]([CH2:33][C:34]2[S:35][C:36]([C:39]3([CH3:44])[O:43][CH2:42][CH2:41][O:40]3)=[CH:37][CH:38]=2)=[N:29]1)=[O:27]>C(Cl)Cl.[Cu](Br)Br>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([CH2:33][C:34]2[S:35][C:36]([C:39]3([CH3:44])[O:43][CH2:42][CH2:41][O:40]3)=[CH:37][CH:38]=2)[O:31][CH:32]=1)=[O:27]
Reactant: COC(=O)C1COC(Cc2ccc(C3(C)OCCO3)s2)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: N#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(Cc2ccc(C3(C)OCCO3)s2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), hexamethylenetetramine (273 mg, 1.92 mmol) and DBU (0.29 mL, 1.92 mmol) were added to a stirred suspension of copper (II) bromide (429 mg, 1.92 mmol) in deoxygenated dry CH2Cl2 (2.0 mL). After 20 min, a deoxygenated solution of 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (240 mg, 0.77 mmol) in CH2Cl2 (5.0 mL) was added and the reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between EA (60 mL), and 40 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH. The aq. layer was extracted with EA (40 mL) and the combined organic layers were washed with 40 mL of a 1:1 mixture of sat. aq. NH4Cl and 25% aq. NH4OH followed by 10% citric acid (40 mL), sat. aq. NaHCO3 (40 mL) and brine (40 mL). The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (2:1→1:4 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:3 hept-EA)=0.40. LC-MS-conditions 01: tR=0.88 min, [M+H]+=309.98.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:22][CH2:23][C:24](N)=[O:25])[CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[OH:28]>[OH-].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([O:22][CH2:23][C:24]([OH:25])=[O:28])[CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: NC(=O)COc1ccc2c(c1)CCCC2NS(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)COc1ccc2c(c1)CCCC2NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
10 mmol of 5-(4-chlorobenzenesulphonylamino)-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetamide are heated under reflux in 12 ml of 2N KOH and 40 ml of MeOH for 6 hours. The methanol is stripped off, 30 ml of 1N KOH are added and the mixture is extracted by shaking twice with CH2Cl2. The H2O phase is brought to pH 2 with concentrated HCl and the precipitate is filtered off and dried thoroughly.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2scnc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4scnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzo[d]thiazole-5-carboxylic acid (Apollo) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.64-7.73 (m, 1 H), 8.35 (s, 1 H), 8.36 (s, 1 H), 8.48 (dt, J=8.1, 2.0, 1.7 Hz, 1 H), 8.83 (dd, J=4.7, 1.7 Hz, 1 H), 9.17 (t, J=1.2 Hz, 1 H), 9.29 (dd, J=2.2, 0.8 Hz, 1 H), 9.66 (s, 1 H) ppm; MS (DCI/NH3) m/z 281 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[C:37]([CH3:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:48][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1C
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-methyl-4-(2-propoxyethoxy)phenyl borate (151 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-[3-methyl-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 75) (261 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[CH:19]([N:22]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[C:26]([CH3:32])[CH:25]=1)([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+]>C(OCC)C.C1COCC1>[CH:34]1([N:22]([CH:19]([CH3:21])[CH3:20])[C:23](=[O:33])[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([OH:31])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[C:26]([CH3:32])[CH:25]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: Cc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2C)cc(OC)c1OC
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (-15° C.) solution Of 3,4,5-trimethoxybromobenzene (965 mg, 3.9 mmol) in ethyl ether (15 ml) is added n-BuLi (3 ml of 1.6 M solution in hexane). The reaction mixture is stirred at -8° C. for 10 min., diluted with THF (5 ml) and warmed to 0° C. After stirring for 5 min., the reaction is cooled to -30° C. and a solution of 4-formyl-3-methylbenzoic acid N-isopropyl-N-cyclohexyl amide (1.12 g, 3.9 mmol) in THF (5 ml) is added. After stirring at -30° C. for 10 min. and warming to room temperature, the reaction is poured onto 0.5 N KHSO4 and extracted with ethyl acetate. The organic layer is washed with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)(=[O:26])[CH3:25]>C(O)C>[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[N:23][NH:22][C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:15]=[C:11]2[N:10]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)c1cccc(C=O)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccncc3)cc2n1
Solvent: CCO
Product: CC(=O)c1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccncc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
There was dissolved, in ethanol (2 mL), (7-morpholin-4-yl-2-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.6 mg, 0.0983 mM), then 3-acetyl-benzaldehyde (14.6 mg, 0.0983 mM) was added to the solution and the mixture was stirred at room temperature overnight. The reaction liquid was filtered and then the resulting solid was washed with diethyl ether to thus give the title compound (33.6 mg, yield: 77%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH2:6][OH:7].CCN(CC)CC.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[Si:22]([O:7][CH2:6][CH2:5][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:3][CH2:2][Cl:1])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCC(O)(CCCl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(O)(CCCl)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a 0° C. solution of 5-chloro-3-phenylpentane-1,3-diol (4.3 g, 20 mmol) and Et3N (3.4 mL, 24 mmol) in 20 mL DMF, was added tert-butyldimethylsilyl chloride (3.3 g, 21 mmol). After stirring for 2 h at 0° C., the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4) and chromatographed (9:1 hex:EtOAc) to provide 1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol (5.2 g, 79%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.32 (m, 4H), 7.25 (m, 1H), 4.88 (s, 1H), 3.73 (dt, 1H, J=10.3, 4.0 Hz), 3.65 (ddd, 1H, J=11.5, 10.6,5.1 Hz), 3.44 (td, 1H, J=10.6, 2.7 Hz), 3.15 (ddd, 1H, J=11.3, 10.6, 5.1 Hz), 2.34 (ddd, 1H, J=13.3, 11.4, 5.1 Hz), 2.27-2.15 (m, 2H), 1.96 (dt, 1H, J=14.6, 3.2 Hz), 0.86 (s, 9H), −0.02 (s, 3H), −0.09 (s, 3H); ESI-MS 351 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[S:13][C:14]3[N:15]=[C:16]([NH2:27])[N:17]=[C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:19]=3[N:20]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](O)=[O:37])=[CH:32][CH:31]=1>>[NH2:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:36](=[O:37])[CH2:35][O:34][C:33]3[CH:39]=[CH:40][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[CH2:25][CH2:26]2)[C:19]2[N:20]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:13][C:14]=2[N:15]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCCCc3ccc(F)cc3)sc2n1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCCCc5ccc(F)cc5)nc34)CC2)cc1
Yield: 35 %

Procedure:
This compound was prepared from 2-(4-(4-fluorophenyl)butyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 35%, according to the procedure for the synthesis of example 50.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
To a stirred solution of 4-bromo-1,2-difluorobenzene (3.5 g, 17.86 mmol) in dry THF was cooled to −78° C., was added a n-BuLi (10.71 mL) solution dropwise. After completion of the addition, the mixture was stirred for 15 min, and triisopropyl borate (6.71 g, 35.71 mmol) was added in one portion. The reaction flask was kept in a cooling bath for 30 min, and warmed to room temperature for 3 hours. The solvent was removed, the residue was dissolved in ether, washed with 1N HCl and water, dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by recrystallization with CH2Cl2 and hexane to give the pure 3,4-difluorophenylboronic acid (800 mg, 20%).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:7]3[CH2:8][CH2:9][C:10]4[O:2][CH:3]=[CH:4][C:5]=4[CH2:6]3)=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.287 g (1.1 mmol) of 4-(4-chlorobenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=4/1/1), after which it was recrystallized from hexane-methanol to yield the desired product.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11]CS.C(OC(=O)C)C>C(O)C.CCCCCC>[N+:5]([CH:4]=[C:3]1[NH:10][CH2:11][CH2:1][S:2]1)([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCS
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C=C1NCCS1
Yield: 46.6 %

Procedure:
TEA (1.8 mL, 13.20 mmol) was added to a solution of 1,1-bis-methylsulfanyl-2-nitro-ethene (I-1b: 1.45 g, 8.802 mmol) and 2-amino-ethanethiol (1 g, 8.802 mmol) in ethanol (20 mL). The resulting mixture was heated to reflux for 3 hours. The reaction mixture was monitored by TLC (70% ethylacetate in hexane). The reaction mixture was concentrated to afford the crude product. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 0.6 g of the product (31% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(SCCc2ccccc2)cc1
Yield: 95 %

Procedure:
A solution of 4-methoxybenzene thiol (5.7 g), triethylamine (4.1 g) and 2-bromoethylbenzene (5.6 ml) in DMF (50 ml) at 0° C. was stirred for 2 h, then added to water and extracted with ether. The solvent was washed with water, 1M NaOH and brine, then dried and evaporated to give the title compound as colourless oil (8.9 g, 95%).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:11]3[CH:18]=[C:17]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:5][CH2:4]1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH2:21][CH2:20][CH2:19][C:17]1[S:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([O:9][CH:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:29])[CH3:1])[CH2:4][CH2:5]3)[C:11]=2[CH:18]=1
Reactant: CN(C)C1CCC(Oc2ncnc3sc(CCNC(=O)OC(C)(C)C)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1CCC(Oc2ncnc3sc(CCN)cc23)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl N-[2-(4-[[4-(dimethylamino)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate (140 mg, 0.33 mmol, 1.00 equiv) in 5 mL of DCM was added CF3COOH (0.5 mL) at room temperature. The resulting solution was stirred for 5 h at ambient temperature and then concentrated under vacuum to give the desired 4-[[6-(2-aminoethyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N,N-dimethylcyclohexan-1-amine trifluoroacetate (100 mg) as a yellow oil which was used directly without further purification. MS (ES): m/z 321 (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].C[Al+]C.[CH3:21][O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].[Cl-].[NH4+]>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([C:8]1[N:9]([CH3:16])[C:10]2[C:15]([C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:28]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CCCCCCc1cn(C)c2ccccc12
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCc1c(C(=O)CCCC(=O)OC)n(C)c2ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of 3-hexyl-1-methyl-1H-indole in methylene chloride at 0° C. was added dimethyl aluminum chloride solution in hexane. The reaction mixture was stirred for 30 minutes. To this solution 4-chlorocarbonyl-butyric acid methyl ester was added at 0 ° C. and the reaction mixture was stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:25][CH:26]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:52]>CO.O1CCOCC1.ClCCCl>[ClH:1].[ClH:52].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:25][CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCNC2CCNC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 3-amino-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (0.101 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The pale orange powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a pale orange powder (0.033 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O.C([O-])(=O)C>CN(C=O)C>[CH2:26]([O:25][C:23]([CH2:22][N:8]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])=[O:24])[CH3:27]
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
Methyl 3-hydroxy-2-(4-nitro-benzenesulfonylamino)-propionate (4.0 g, 13.1 mmol) and potassium carbonate anhydride (5.45 g, 39.4 mmol) were suspended in DMF (25 mL), and ethyl bromoacetate (2.91 mL, 26.3 mmol) was added dropwise at 0° C. After stirring for 4 hours, 50 mL of distilled water and 100 mL of acetate were introduced and stirred to separate layers. The supernatant was washed with 50 mL of a 5% Na2S2O3 aqueous solution, 50 mL of a 1N HCl aqueous solution, 50 mL of a saturated NaHCO3 aqueous solution, and 100 mL of distilled water, and it was dried and concentrated under reduced pressure. The mixture was separated with hexane and ethylacetate (2:1) in a silica gel column to obtain a yellow oil (4.43 g, 86.5).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1C=CC=C[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>C(O)C.C(#N)C.[C].[Pd]>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC#N
Solvent: CCO
Product: C=CCON1C(=O)N2C[C@H]1CC[C@H]2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
140 mg (0.421 mmol) of (2S,5R)-tert-butyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate was dissolved in ethanol (3.1 mL), and 14 mg of 10% palladium-carbon (50% water content) was added, followed by stirring at room temperature for 1 hour under hydrogen atmosphere. The catalyst of the reaction mixture was filtered through celite, and the residue resulting from concentration of the solvent under reduced pressure was dissolved in acetonitrile (4.1 mL), and 62 mg (0.449 mmol) of anhydrous potassium carbonate and 70 μL (0.809 mmol) of allyl bromide were added, followed by stifling at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed sequentially with water, saturated aqueous ammonium chloride solution and saturated brine, subsequently the organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was applied to silica gel column chromatography (n-hexane/ethyl acetate=5/2) to afford 60.8 mg of the title compound (yield 54%). Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 4.8 min.).