Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC1C=C2C(=CC=1C(F)(F)F)N(C(=O)NC1C=CC=C(C(O)=O)C=1)CC2.[CH3:28][S:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][C:38]=1[C:39]([F:42])([F:41])[F:40])[N:35]([C:43](=[O:56])[NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([O:53]CC)=[O:52])=[CH:47][CH:46]=1)[CH2:34][CH2:33]2>>[CH3:28][S:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][C:38]=1[C:39]([F:40])([F:41])[F:42])[N:35]([C:43](=[O:56])[NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([OH:53])=[O:52])=[CH:47][CH:46]=1)[CH2:34][CH2:33]2
Reactant: CCOC(=O)c1ccc(NC(=O)N2CCc3cc(SC)c(C(F)(F)F)cc32)cc1
Agent: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)O)c1)CC2
Product: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(C(=O)O)cc1)CC2
Yield: 88 %

Procedure:
This was made in the same manner as 5-methylthio-6-trifluoromethyl-1-(3-carboxy phenyl carbamoyl)indoline using 5-methylthio-6-trifluoromethyl-1-(4-ethoxycarbonyl phenyl carbamoyl)indoline to give the product as a pale green solid (2.455 g, 88%), mp>200° C.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:25][CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CC1CCO
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.4 %

Procedure:
To a solution of the TBDPS-protected alcohol 11b (320 mg, 0.588 mmol) in dry THF (5 mL) at 0° C. was added TBAF (1.0M/THF, 0.74 mL, 0.735 mmol), and the reaction mixture was allowed to warm to rt while stirring under argon for 7 h, then quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 5:5, hexanes/EtOAc) afforded 166 mg (92%) of the title compound as a colorless oil. [α]D23 −21.6 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 7.42-7.28 (m, 5H), 5.10 (m, 2H), 4.76 (appbd, 1H, J=5.7 Hz), 3.63 (bs, 2H), 3.04 (m, 1H), 2.12-1.98 (bs, 1H), 1.83-1.62 (m, 2H), 1.42 (t, 2H, J=7.0 Hz), 1.16-0.95 (m, 2H), 0.90 (appt, 6H, J=7.0 Hz), 0.53 (sept, 1H, J=4.3 Hz), 0.42 (dt, 1H, J=8.4, 4.5 Hz), 0.34 (dt, 1H, J=8.4, 5.0 Hz); HRMS (ESI) m/z calcd for C18H27NO3Na 328.1889, found 328.1860.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH:3]=[CH:4][CH3:5].[C:9](OC)(=[O:14])/C=C/CC.C(OC)(=O)/C=C\CC.C(OC)(=O)CCC=C>>[CH3:9][O:14][CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: CC/C=C/C(=O)OC
Reactant: CC=CCC(=O)OC
Agent: C=CCCC(=O)OC
Agent: CC/C=C\C(=O)OC
Product: CCC(CC(=O)OC)OC
Yield: 3 %

Procedure:
10 g/hour of methyl 3-methoxyvalerate were pumed into an evaporator and passed from there, in gaseous form together with 3 l of nitrogen, at 350° C., over 5 g of an SiO2 catalyst. The gaseous reaction products were condensed, weighed and analysed by gas chromatography. In the course of 6 hours, 53.3 g of the reacted mixture consisting of 30% of methyl 3-pentenoate, 56% of methyl 2-transpentenoate, 8% of methyl 2-cis-pentenoate, 2% of methyl 4-pentenoate and 3% of unconverted methyl 3-methoxyvalerate were obtained. The ratio of 3-pentenoates to 2-pentenoates was accordingly 1:2.2.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[N:15]([CH2:19][CH2:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[O:22])[CH:16]=[CH:17][N:18]=1.IC>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][CH:20]([CH2:19][N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH3:13])[C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH3:32])[CH:24]=1)=[O:22]
Reactant: Cc1nccn1CCC(=O)c1cn(C)c2ccccc12
Reactant: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1nccn1CC(C)C(=O)c1cn(C)c2ccccc12
Temperature: 25 °C

Procedure:
n-Butyllithium (1.6M in hexane; 10 ml) was added dropwise to a stirred solution of diisopropylamine (1.6 ml) in dry THF (40 ml) at 0° under nitrogen. After 40 min at 0° the reaction was cooled to -70° and treated dropwise with a solution of 3-(2-methyl-1H-imidazol-1-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone (2.7 g) in dry THF (150 ml) over 45 min. After a further 30 min a solution of iodomethane (0.7 ml) in hexamethylphosphoramide (1.5 ml) was added, and the suspension was allowed to warm to room temperature over 2.5 h. The suspension was partitioned between sodium carbonate (2N; 150 ml) and ethyl acetate (2×100 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil which was purified by column chromatography eluting with System B to give the free base of the title compound as an oil (2.05 g). A sample (0.5 g) of the free base was dissolved in absolute ethanol (5 ml) acidified with ethanolic hydrogen chloride, and the salt was precipitated by diluting with excess dry ether (ca. 200 ml). The salt was filtered off, and dried in vacuo to give the title compound (0.25 g), m.p. 205°-207°.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[Si](OC1C=CC(N)=CC=1)(C(C)(C)C)(C)C.[NH2:31][C:32]1[N:36]([CH3:37])[N:35]=[C:34]([C:38]#[N:39])[CH:33]=1>>[Si:7]([O:6][C:5]1[CH:14]=[CH:15][C:2]([NH:31][C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]#[N:39])[CH:33]=2)=[CH:3][CH:4]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: Cn1nc(C#N)cc1N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Product: Cn1nc(C#N)cc1Nc1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
The procedure is in accordance with the protocol of Step B of Preparation 1″, replacing the 4-bromo-1-methyl-1H-pyrazole by (4-bromophenoxy)-(tert-butyl)dimethyl-silane and the 4-{[tert-butyl(dimethyl)silyl]oxy}aniline by the compound from Step A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.Cl.C(O)C>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.4 %

Procedure:
In dichloromethane (50 ml) was dissolved t-butyl 4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-1-piperidinecarboxylate (1.56 g, 3.21 mmol). Trifluoroacetic acid (5.0 ml) was added dropwise to the resulting solution under ice cooling. The reaction mixture was stirred at room temperature for 2 hours and then, concentrated under reduced pressure. To the residue thus obtained were added dichloromethane (10 ml) and a 1N hydrochloric acid-ethanol solution (10 ml). The resulting mixture was concentrated under reduced pressure to give a white solid. The resulting solid was washed with diethyl ether to give the title compound (1.36 g, 3.12 mmol, 97%) as a white powder.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[S:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[N:14]1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:16]1[N:15]=[N:14][S:13][CH:17]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1csnn1
Product: S=C(NN=Cc1csnn1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (35 mg, 0.21 mmol) and 1,2,3-thiadiazole-4-carboxaldehyde (33mg, 0.287 mmol) similar to Example 3 and isolated as a white solid (47 mg, 80%). 1H NMR (CDCl3): 9.95 (s, 1H), 8.85 (s, 1H), 7.70 (brs, 1H), 6.16 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 4.27 (t, J=8.7 Hz, 1H), 3.06 (s, 1H), 2.96 (s, 1H), 1.92 (ddd, J=7.6, 7.0, 2.4 Hz, 1H), 1.67 (m, 1H), 1.51-1.40 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1>C1COCC1.O.CCOC(C)=O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,2,2-Trifluoroethanol (0.35 mL, 4.80 mmol) was dissolved in THF (2 mL) and cooled to 0 C under nitrogen. Sodium hydride (60% dispersion in mineral oil, 0.192 g, 4.80 mmol) was added portionwise and the mixture stirred for 10 min. A solution of methyl 4-(bromomethyl)benzoate in THF (3 mL) was added, the mixture was warmed to room temperature and then heated to 50 C for 3 h. The mixture was then diluted with water (15 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous neutralised with 1M hydrochloric acid. The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a colourless oily residue (1.05 g, 97%). 1H NMR (500 MHZ, CDCl3) δ ppm 7.95 (2H, d), 7.33 (2H, d), 4.64 (2H, s), 3.83 (3H, s) and 3.77 (2H, q).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([O:13][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1CCN(c2ccc(Br)cc2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
(S)-1-(4-Bromo-phenyl)-pyrrolidin-3-ol (14.0 g, 57.7 mmol) was dissolved in DMF (100 mL), and TBDMS-Cl (10.4 g, 69.2 mmol) and imidazole (9.81 g, 144 mmol) were added. The mixture was stirred at rt overnight. Aq. sat. NH4Cl (100 mL) was added, and the mixture was extracted with heptane (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:15→1:4) yielded the title compound (17.3 g, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:12](#[N:16])[CH2:13][CH2:14][CH3:15].Cl.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:11][C:12](=[NH:16])[CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccn1N
Reactant: CCCC#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCC(=N)Nn1cccc1C(=O)OCC
Temperature: 75 °C
Yield: 74.1 %

Procedure:
To a solution of 1-amino-1H-pyrrole-2-carboxylic acid ethyl ester (10.8 g, 70.1 mmol) in 250 mL of dioxane in a sealed tube at room temperature was added butyronitrile (61 mL, 700 mmol) followed by 4 N HCl in dioxane (70 mL, 280 mmol). The tube was flushed with Ar, sealed, and heated at 75° C. for 14 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and then diluted with 240 mL of dioxane. Triethylamine (78 mL, 560 mmol) was added and the reaction was heated at 75° C. for 6 h. After cooling to room temperature, the reaction was concentrated in vacuo to give the crude product. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 1:1) gave the title compound as a light brown solid (11.6 g, 74%): 1H NMR (CDCl3) δ 6.80 (q, 1H, J=1.96 Hz), 6.59 (t, 1H, J=2.16 Hz), 6.03 (q, 1H, J=2.6 Hz), 4.54 (brs, 2H), 4.11 (q, 2H, J=7.12 Hz), 2.27 (t, 2H, J=7.96 Hz), 1.66 (hex, 2H, J=7.72 Hz), 1.19 (t, 3H, J=7.12 Hz), 0.95 (t, 3H, J=7.32 Hz); 13C NMR (CDCl3) δ 166.7, 160.2, 124.8, 119.8, 116.0, 107.2, 60.0, 35.6, 20.6, 14.9, 14.1; MS (ESI+) 224.10 (M++H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][N:4]=1.Br(O)(=O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][N:4]=1
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Br+2]([O-])O
Solvent: O
Product: CNc1ccc(-c2nc3ccc(O)cc3s2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
2-[2-(N-Monomethyl)aminopyridin-5-yl]-6-methoxybenzothiazole (42, 650 mg, 2.40 mmol) obtained in step 3 was dissolved in [bmim][BF4] (13 mL) and, after adding bromic acid (48%, 2.4 mL), the reaction mixture was held at 130° C. overnight. After cooling to room temperature and adding water and sodium bicarbonate aqueous solution, the solid thus obtained was filtered and washed with water. After removing the solvent under reduced pressure, recrystallization from methanol and dichloromethane solvent yielded 2-[2-(N-monomethyl)aminopyridin-5-yl]-6-hydroxybenzothiazole (46, 550 mg, 89%) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1.[H-].[Na+].[CH3:26][O:27][CH2:28]Cl>CN(C=O)C>[CH3:26][O:27][CH2:28][O:1][C:2]1[C:7]2[C:8]([CH3:18])=[C:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1
Reactant: COCCl
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCCO)=C2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1cc(OCOC)c2c(c1)OC(C)(C)C(CCCO)=C2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 1.96 g (6.16 mmol) of 5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol in 10 mL of anhy. DMF (Aldrich) under argon at RT was added 260 mg (~1.05 eq.) of a 60% dispersion of sodium hydride (Aldrich) and the mixture stirred at RT under argon until effervescence had ceased and the solution had become a clear, darker colored solution. To the stirred solution was added 0.55 mL (~1 eq.) of methoxymethyl chloride (Aldrich, 85% purity technical grade) by syringe directly into the solution with the needle tip below the surface of the solution. The color of the reaction mixture discharged and a precipitate formed within 1 min. Stirring was continued for 0.5 hr. Half of the solution was then withdrawn by syringe for use in another reaction. The remaining half was poured into a mixture of 50 mL of sat. aq. NaHCO3 and 100 mL EtOAc, the mixture shaken well and sufficient water added to dissolve solids that formed to give two clear phases. The phases were separated and the organic phase washed with half-sat. aq. NaCl (2×50 mL), sat. aq. NaCl (1×50 mL), dried (Na2SO4), evaporated under reduced pressure and the residue dried under high vacuum to give 1.05 g (~94%) of the desired product 5-(Methoxymethoxy)-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol as an oil, shown by 1H-NMR to be of good purity.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([N:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:29]3[CH2:30][CH2:31][N:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:27][CH2:28]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CCN(C2CCCCC2)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(C2CCCCC2)CC1
Yield: 72 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-cyclohexyltetrahydro-4(1H)-pyridinone using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-cyclohexyl-piperidin-4-yl)-methyl-amine as a solid (72% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethylether and methanol to give 345 as a solid (76% yield). NMR (CDCl3, 400 MHz), 1.06-1.21 (5H, m), 1.51-1.57 (3H, m), 1.74-1.81 (6H, m), 2.12-2.18 (3H, m), 2.24 (3H, s), 2.41-2.47 (1H, m), 2.94-2.96 (2H, m), 3.84 (4H, t, J=4.4), 3.87 (2H, s), 3.99 (4H, t, J=4.4), 5.26 (2H, s), 7.21 (1H, s), 9.25 (2H, s). MS: (ESI+): MH+=523
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: C1CCNCC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 101) (220 mg, 0.49 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with piperidine in DMF according to the method described in Example 45. Obtained as a light brown solid (250 mg, 99%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][O:18][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ncccc2OCCO)CC1

Procedure:
The title compound was prepared starting from 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 0.67 g, 2.6 mmol) and tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.66 g, 2.9 mmol) according to the procedure in Example 23, Step 1, followed by removing the tetrahydropyranyl protecting group according to the procedure given in Example 23, Step 2. Yield 0.36 g (38%). MS (ESI+) for C18H29N3O5 m/z 368.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:18][O:19][C:20](=[O:38])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:38])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH:26][CH:25]=1)[NH:22][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2OC)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(C(=O)OC(C)(C)C)cc1Cl

Procedure:
2-Chloro-4-(tert-butoxycarbonyl)benzoic acid was coupled with 4-(2-methoxyphenyl)-L-phenylalanine methyl ester (free amine from Example 1-3)) using a similar procedure as described in Example 2-1) to give N-[2-chloro-4-(tert-butoxycarbonyl)benzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (0.332 g).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:31]([CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1)[CH2:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH2:31][CH2:32][CH3:33])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCCC1CCCN1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 35.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2-propylpyrrolidine (113 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 120° C. for 10 min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was then added and the reaction was reacted at room temperature overnight. It was then purified by Gilson Preparatory HPLC to give 21.0 mg of the title compound (38.7%).
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1C(=O)CCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C(OCC)(=O)C.CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18]([N:5]2[CH2:6][CH2:7][C:2]([OH:8])([CH3:1])[CH2:3][CH2:4]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC1(O)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(O)CCN([C@@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-Methyl-piperidin-4-ol (2.2 g) and (S)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g) in acetonitrile (54 mL)/NMP (30 mL)/DMF (5 mL) was added potassium carbonate (9.2 g). The mixture was stirred at 80° C. for 12 h. Ethyl acetate and water was added. The aqueous phase was acidified, extracted with ethyl acetate. The collected organic phase were washed with water, dried over sodium sulfate and concentrated. The product with the molecular weight of 284.40 (C15H28N2O3) was obtained in this way; MS (ESI): 285 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=C[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.NN.Cl>C(O)C.O>[NH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[SH:10]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1S
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of 6-nitrobenzo[d]thiazole (5 g, 27.7 mmol) in ethanol (45 mL) was added hydrazine hydrate (8.10 mL, 166 mmol). The resulting mixture (dark red) was stirred overnight at room temperature. The mixture was then acidified by the slow, careful addition of 3M HCl in water (50 mL). This mixture was further diluted with water (50 mL), and the resulting yellow/orange precipitate was extracted with dichloromethane (3×). The combined organics were dried, filtered, and concentrated, giving an orange solid (4.62 g, 98%). 1H NMR (DMSO-d6) δ 8.12-8.09 (m, 1H), 7.88-7.85 (m, 1H), 6.75-6.71 (m, 1H), 6.28 (brs, 2H); ESI-MS (m/z, %): 170 (MH+, 100).