Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([CH3:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=1.C(O)(=O)C(C(C(O)=O)O)O>C1COCC1>[NH2:12][CH:13]([CH3:19])[CH:14]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)CC(C)N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cccc(C#N)c1)C(C)N
Temperature: -20 °C
Reaction time: 8 h
Yield: 128.5 %

Procedure:
To a suspension of methyl β-aminobutyrate p-toluenesulfonic acid salt (4 g, 13.8 mmol) in THF cooled to −20 ° C. was added LiHMDS (28.4 mmol, 2.05 eq.) A THF solution of α-bromo m-tolunitrile (2.57 g, 13.1 mmol) was added. Upon completion the reaction was quenched with 5% NaHCO3 and concentrated. The residue was partitioned between water and methyl propi-onate. The water layer was extracted with another portion of methyl propionate. The combined organic layer was dried over MgSO4 and filtered. To the filtrate, tartaric acid (2.95 g, 19.66 mmol) was added and stirred overnight. The solid was filtered, washed with methyl propionate, and dried to yield the tartaric salt of methyl β-amino-α-(3-cyanophenylmethyl)butyrate (3.91 g, 74% yield). HPLC and NMR confirm formation of the desired product. 1H NMR for the tartrate salt: (500 MHz, DMSO) δ 7.71-7.51 (m, 4H), 4.32 (s, 2H), 3.53 (overlapping multiplet and a singlet, 4 H). HPLC indicated purity >99% and the diastereomer ratio to be 17:1 anti:syn (R,R:R,S). β-amino-α-(3-cyanophenylmethyl)butyrate is the anti diastereomer.
Reaction SMILES: [C:1]1([C:7]2[C:11](C(F)(F)F)=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[CH2:30])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)ON=2)C=CC=C[CH:2]=1.BrC1C=C2C(=CC=1)C1SC(CCCCC)=NC=1CC2>>[CH2:10]([C:16]1[S:17][C:18]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=[CH2:30])=[CH:26][CH:27]=3)[CH2:22][CH2:21][C:19]=2[N:20]=1)[CH2:11][CH2:7][CH2:1][CH3:2]
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Agent: CCCCCc1nc2c(s1)-c1ccc(Br)cc1CC2
Product: C=Cc1ccc2c(c1)CCc1nc(CCCCC)sc1-2

Procedure:
This compound was prepared according to the procedure described for Preparation 82E, employing 270 mgs of 7-bromo-2-pentyl-4,5-dihydronaphtho[2,1-d]thiazole (Preparation 86B). Yield: (193 mgs, 85%). LC/MS M+1=337.
Reaction SMILES: COC([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6]1=[O:18])=O>C(O)(=O)C>[N:7]1([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][CH2:9][C:10](=[O:11])[CH2:5][C:6]1=[O:18]
Reactant: COC(=O)C1C(=O)CCN(N2CCCCC2)C1=O
Solvent: CC(=O)O
Product: O=C1CCN(N2CCCCC2)C(=O)C1
Yield: 36 %

Procedure:
The ethyl ester product from step 3 was dissolved in 10% acetic acid (250 ml) and the solution boiled under reflux for one hour. The cooled reaction mixture was evaporated, and the residue purified by flash chromatography (CH2Cl2: acetone 9:1-1:1) to give 4.00 g (36%) of the title compound as a semi-solid.
Reaction SMILES: ClC1C=C2C(C(N3CCN(C(NC4C=CC(C(F)(F)F)=CC=4)=O)CC3)=CC=N2)=CC=1.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]=[C:67]=[O:68])=[CH:62][CH:61]=1)([CH3:59])[CH3:58]>C(Cl)Cl.CO>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][N:45]([C:67]([NH:66][C:63]4[CH:64]=[CH:65][C:60]([CH:57]([CH3:59])[CH3:58])=[CH:61][CH:62]=4)=[O:68])[CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: CC(C)c1ccc(N=C=O)cc1
Agent: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (150 mg, 0.61 mmol), diisopropyl(ethyl)amine (158 mg, 1.22 mmol), and 4-isopropylphenyl isocyanate (117 mg, 0.73 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.CS(C)=O.[C@H:28]1([NH2:35])[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1>C(OCC)(=O)C>[NH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([NH:35][C:18]2[CH:17]=[C:16]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH:8][CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:4]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:29][CH2:30]1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (Intermediate G) (250 mg, 0.702 mmol) was added DMSO (3 ml) and trans-cyclohexane-1,4-diamine (952 mg, 6.32 mmol). The reaction mixture was stirred at 100° C. for 20 hours and the reaction progress was followed by LCMS. The reaction mixture was cooled, diluted with 250 ml ethyl acetate, washed with saturated sodium bicarbonate (1×), water (3×) and concentrated to constant mass, giving 320 mg of product as a free base, which was used without further purification. A portion of the title compound, 25 mg was purified by prep LC and lyophilized to give 17.6 mg of the title compound as a TFA salt. LCMS (m/z): 450.2 (MH+), retention time=0.58 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.16-1.76 (m, 8 H) 1.76-1.98 (m, 1 H) 2.04-2.27 (m, 4 H) 3.06-3.16 (m, 1 H) 3.19 (d, J=6.74 Hz, 2 H) 3.37 (t, J=11.87 Hz, 2 H) 3.62-3.77 (m, 1 H) 3.92 (dd, J=1.28, 3.08 Hz, 2 H) 6.61 (d, J=8.79 Hz, 1 H) 6.73 (s, 1 H) 7.50 (d, J=9.08 Hz, 1 H) 8.04 (s, 1 H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]12[CH2:57][CH:52]3[CH2:53][CH:54]([CH2:56][C:50]([CH2:58][OH:59])([CH2:51]3)[CH2:49]1)[CH2:55]2>>[Cl:17][C:18]1[C:19]([O:59][CH2:58][C:50]23[CH2:51][CH:52]4[CH2:53][CH:54]([CH2:55][C:48]([F:47])([CH2:57]4)[CH2:49]2)[CH2:56]3)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC12CC3CC(CC(F)(C3)C1)C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(F)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 3-fluoroadamantan-1-yl methanol, the title compound was obtained as a colorless solid (0.16 g, 35%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 3.84 (s, 2H), 2.87 (s, 6H), 2.30 (br s, 2H), 1.87-1.76 (m, 6H), 1.61-1.52 (m, 6H); MS (ES−) m/z 461.1, 463.1 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)C(C)C)C>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:6]2[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc(Cl)c2Cl)CC1

Procedure:
A solution of 2,4,5,6-tetrachloro-pyrimidine (1.67 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.85 g (29%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.49-1.60 (m, 2H), 1.73-1.77 (m, 2H), 2.81 (br s, 2H), 3.95-3.98 (m, 2H), 4.09-4.16 (m, 1H), 7.88 (d, J=8.0 Hz, 1H). 13C NMR (100 MHz, DMSO): δ 28.07, 30.45, 43.33, 48.90, 78.65, 109.37, 153.80, 154.62, 155.66, 158.74. MS (ISP): 383.0 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:10]([CH:12]([N:20]2[CH2:25][CH2:24][CH:23]3[S:26][C:27](=[O:29])[CH:28]=[C:22]3[CH2:21]2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])[CH2:9][CH2:8]1.[H-].[Na+].[C:32](OCC)(=[O:34])[CH3:33]>CN(C)C=O.C(OC(=O)C)(=O)C>[C:32]([O:29][C:27]1[S:26][C:23]2[CH2:24][CH2:25][N:20]([CH:12]([C:10]([CH:7]3[CH2:8][CH2:9]3)=[O:11])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH2:21][C:22]=2[CH:28]=1)(=[O:34])[CH3:33]
Reactant: O=C1C=C2CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Reaction time: 0.33 h
Yield: 65 %

Procedure:
2.6 g (7.8 mmole) of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine pyridine (prepared as described in Example 20) were dissolved in a mixture of 10 ml of dimethylformamide and 5 ml of acetic anhydride, and then 0.35 g (8.6 mmole) of a 60% w/w dispersion of sodium hydride in mineral oil was added to the resulting solution, whilst ice-cooling; the mixture was then stirred for 20 minutes at the same temperature, after which it was stirred for a further 3 hours at room temperature. At the end of this time, 300 ml of ethyl acetate were added to the mixture, which was then washed four times, each time with 50 ml of a saturated aqueous solution of sodium chloride The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, using a 100:3 by volume mixture of toluene and ethyl acetate as the eluent, to give a yellow oil. This oil was crystallized from diisopropyl ether, to obtain the title compound as white crystals, melting at 120°-121.5° C., in a yield of 65%.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]([C:15]([NH2:17])=[S:16])[NH:12][CH:13]=O.Cl>[OH-].[Na+]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15](=[S:16])[NH:17][CH:13]=[N:12]1
Reactant: NC(=S)N(NC=O)C1CCc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: S=c1[nH]cnn1C1CCc2ccccc2C1
Yield: 44.2 %

Procedure:
A solution of N-[(1,2,3,4-tetrahydronaphthalen-2-yl)(aminothiocarbonyl)amino]formamide (0.6 g, 2.4 mmol) in 10 mL of 10% sodium hydroxide was heated at 70° C. for 30 minutes. The solution was cooled, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate/hexane and filtration gave 2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro[1,2,4]triazole-3-thione (0.25 g. 1.06 mmol), m.p. 200.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].C(O)(=[O:13])C>>[CH3:1][C:2]([C@@H:3]1[CH2:9][CH:8]=[C:6]([CH2:7][OH:13])[CH2:5][CH2:4]1)=[CH2:10]
Reactant: CC(=O)O
Reactant: C=C1CCC2CC1C2(C)C
Product: C=C(C)[C@@H]1CC=C(CO)CC1
Yield: 40 %

Procedure:
The solvent system must be polar. If the non-polar beta-pinene is used in excess as the solvent, the reaction products are only polymeric substances. For reasons not apparent, if the solvent is glacial acetic acid alone, a completely polar solvent system, perillyl alcohol is obtained in only about a 40% yield.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C@:14]2([CH3:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:16][C@@H:15]2[CH3:29])[CH:11]=[CH:12][CH:13]=1)=[O:7].Cl>O.O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]([C@:14]2([CH3:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:16][C@@H:15]2[CH3:29])[CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cccc([C@]2(C)CCN(C(=O)OCC[Si](C)(C)C)C[C@@H]2C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OCC[Si](C)(C)C)CC[C@@]1(C)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 97.2 %

Procedure:
A solution of lithium hydroxide monohydrate (2.75 g, 0.065 mol, 6 eq) in water (20 mL) was added drop wise to a cold (0° C.) solution of (6) (4.28 g, 0.0109 mol, 1 eq) in tetrahydrofuran (40 mL). The mixture was allowed to warm to room temperature and stirring was continued for 5 days. A 1N aqueous HCl solution (100 mL) was added to the mixture which was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL) and dried over sodium sulfate. Evaporation of the solvent afforded the desired compound (4.0 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13](=[O:16])[CH:14]=[CH2:15].[OH-].[Na+]>CCOC(C)=O.O.[Fe]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=1
Reactant: C=CC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)Nc1cc(N)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(2-methoxy-5-nitro-phenyl)-acrylamide (Step 1) (335 mg, 1.51 mmol), iron powder (0.51 g, 9.0 mmol), FeSO4 (839 mg, 3.02 mmol), Celite® (0.3 g) and water (9 mL) was heated to reflux with stirring for 3 h. The reaction mixture was cooled to RT. The solution was made basic to pH 13-14 by the addition of 2 N NaOH. The reaction mixture was diluted with EtOAc and water. The solution was filtered to remove the solids and solids were washed with EtOAc. The aqueous layer was extracted three times with EtOAc (100 mL) and the combined organics were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography using EtOAc as the solvent to give N-(5-amino-2-methoxyphenyl)-acrylamide.
Reaction SMILES: O=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]([O:15]C)=O.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:13](=[O:15])[CH2:12][CH:3]3[C:2]([C:11]4[CH:10]=[N:9][CH:8]=[CH:7][C:6]=4[CH2:5][CH2:4]3)=[N:26]2)=[CH:23][CH:24]=1
Reactant: COC(=O)CC1CCc2ccncc2C1=O
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: O=C1CC2CCc3ccncc3C2=NN1c1ccc(C(F)(F)F)cc1
Yield: 15.9 %

Procedure:
Methyl 5,6,7,8-tetrahydro-8-oxoisoquinolin-7-acetate (1.0 g), 4-trifluoromethyl-phenylhydrazine (1.6 g) and para-toluenesulphonic acid (0.25 g) were heated under reflux in xylene (20 ml) for 4 hours. The cooled reaction was poured into 2M sodium hydroxide solution and extracted with ethyl acetate, which was then washed with brine, dried, and evaporated to a gum. The gum was chromatographed on silica gel, eluting with ethyl acetate-isohexane (1:1), to afford a solid which was crystallised from isopropanol-isohexane to yield the title compound (0.25 g),
Reaction SMILES: C(OC(=O)NCC1CCNCC1)(C)(C)C.C(OC(=O)[NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30](=[O:49])[NH:31][C:32]2[S:33][C:34]3[C:40]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:39][CH:38]=[C:37]([O:47][CH3:48])[C:35]=3[N:36]=2)[CH2:26][CH2:25]1)(C)(C)C.FC(F)(F)C(O)=O.[CH3:58][S:59](Cl)(=[O:61])=[O:60].N1C=CC=CC=1>>[CH3:48][O:47][C:37]1[C:35]2[N:36]=[C:32]([NH:31][C:30]([N:27]3[CH2:26][CH2:25][CH:24]([CH2:23][NH:22][S:59]([CH3:58])(=[O:61])=[O:60])[CH2:29][CH2:28]3)=[O:49])[S:33][C:34]=2[C:40]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)=[CH:39][CH:38]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(CNC(=O)OC(C)(C)C)CC3)nc12
Agent: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(CNS(C)(=O)=O)CC3)nc12

Procedure:
Using piperidin-4-ylmethyl-carbamic acid tert-butyl ester, [1-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester was prepared as white solid. Subsequent deprotection with trifluoroacetic acid and reaction with methanesulfonyl chloride/pyridine under standard conditions afforded the title compound as white crystals in 44% overall yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9]Br)=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>ClCCl>[Br:1][C:2]1[C:3]([CH2:9][NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[N:4][C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)c(CBr)n1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CNCc2nc(F)ccc2Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of 3-bromo-2-bromomethyl-6-fluoro-pyridine (2.70 g, 10.0 mmol, 1.0 equiv) in dichloromethane (20 mL) was added a solution of 4-methoxybenzylamine (2.74 g, 20.0 mmol, 2.0 equiv) in dichloromethane (5 mL) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-50%) to afford (3-bromo-6-fluoro-pyridin-2-ylmethyl)-(4-methoxy-benzyl)-amine (1.2 g). MS: [M+H]+=326.
Reaction SMILES: [I-:1].[Na+].[C:3](=[O:18])([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)[O:4][CH:5](Cl)[CH3:6]>C(#N)C>[C:3](=[O:18])([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)[O:4][CH:5]([I:1])[CH3:6]
Reactant: [I-]
Reactant: CC1CC(OC(=O)OC(C)Cl)CC(C)(C)C1
Agent: [Na+]
Solvent: CC#N
Product: CC1CC(OC(=O)OC(C)I)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetonitrile (250 ml) is warmed to 50° C. and 38 g of sodium iodide is added and dissolved, followed by addition of 14 g of 1-chloroethyl 3,3,5-trimethylcyclohexyl carbonate. The mixture is stirred for 2 hours, poured into 250 ml of ice-water and extracted with two 200-ml portions of ethyl acetate. The extracts are combined, washed with 150 ml of 5% aqueous sodium thiosulfate, 300 ml of water and 300 ml of saturated aqueous sodium chloride (twice) in that order and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure to to give the title compound as oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:44][C:45]1[C:46]([CH3:55])=[C:47]([CH2:51][C:52](O)=[O:53])[CH:48]=[CH:49][CH:50]=1.CCN(C(C)C)C(C)C>O.CN(C)C=O>[F:44][C:45]1[C:46]([CH3:55])=[C:47]([CH2:51][C:52]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[S:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:53])[CH:48]=[CH:49][CH:50]=1
Reactant: Cc1c(F)cccc1CC(=O)O
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cccc1CC(=O)N1CCc2cc(-c3csc4ccnc(N)c34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.329 mmol) followed by HATU (125 mg, 0.329 mmol), 3-Fluoro-2-methylphenyl acetic acid (55.4 mg, 0.329 mmol) and DIEA (0.230 mL, 1.317 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-{1-[(3-fluoro-2-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (94.6 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (d, J=8.1 Hz, 1H) 7.83 (d, J=5.8 Hz, 1H) 7.41 (s, 1H) 7.35 (s, 1H) 7.26 (d, J=5.6 Hz, 1H) 7.14-7.25 (m, 2H) 7.02-7.11 (m, 2H) 5.42 (br. s., 2H) 4.31 (t, J=8.5 Hz, 2H) 3.97 (s, 2H) 3.27 (t, 2H) 2.15 (m, 3H).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH:11]1[C:19]2[C:14](=[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:36])[C@H:27]([NH2:35])[CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:22][CH2:21]3)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.N1(C2C=CC=C3C=2C=CN3)CCNCC1.C(OC(N[C@H](CC1C=CC=CN=1)C(O)=O)=O)(C)(C)C>C1COCC1.C(OCC)(=O)C>[NH:11]1[C:19]2[C:14](=[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:36])[C@H:27]([NH:35][CH:1]=[O:2])[CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:22][CH2:21]3)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: O=CO
Reactant: N[C@H](Cc1ccccn1)C(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Agent: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)O
Agent: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@H](Cc1ccccn1)C(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of formic acid (0.9 mL; 24 mmol) and acetic anhydride (1.8 mL; 19.5 mmol) was stirred at 60° C. for 4 hours, then cooled to ambient temperature. The resulting mixed anhydride was added to a −10° C. solution of (1R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]-2-oxo-1-(pyridin-2-ylmethyl)ethylamine (prepared in two steps from 4-piperazin-1-yl-1H-indole and (2R)-2-[(tert-butoxycarbonyl)amino]-3-pyridin-2-ylpropanoic acid according to the procedures outlined in examples 1 and 2) (1.07 g.; 3.0 mmol) in THF (30 mL). The mixture was allowed to warm to ambient temperature over 3 hours, diluted with ethyl acetate, and washed with saturated aqueous Na2CO3. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography to afford the title compound as a beige solid foam (720 mg.; 64%). MS EI M+.@ m/z 377; 1H NMR, 400 MHz, DMSO-d6.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccncc2c1O
Product: CCOC(=O)c1cnc2ccncc2c1Cl

Procedure:
A mixture of 9.3 g of ethyl 4-hydroxy-1,6-naphthyridine-3-carboxylate (prepared according to J. Org. Chem. 15, 1224 (1950)) and 56 ml of phosphorous oxychloride is refluxed for 2 hours 40 minutes, then evaporated to dryness and the residue is treated with cold dilute ammonium hydroxide and methylene chloride. Insoluble material is removed by filtration, then organic layer is separated, washed with brine, dried over sodium sulfate and evaporated to dryness to yield ethyl 4-chloro-1,6-naphthyridine-3-carboxylate.