Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=459.1.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]([O:14][CH:15]3[CH2:18][N:17]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:16]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:36](Cl)(=[O:39])[O:37][CH3:38]>C(Cl)Cl>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[N:17]1[CH2:18][CH:15]([O:14][C:9]2[C:8]([CH:5]3[CH2:6][CH2:7][N:2]([C:36]([O:37][CH3:38])=[O:39])[CH2:3][CH2:4]3)=[N:13][CH:12]=[CH:11][N:10]=2)[CH2:16]1
Reactant: c1ccc2nc(N3CC(Oc4nccnc4C4CCNCC4)C3)ccc2c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 2-(3-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)azetidin-1-yl)quinoline hydrochloride (see PREPARATION P4.1; 100 mg, 0.29 mmol) in dry DCM (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and methyl carbonochloridate (54 mg, 0.58 mmol) was added dropped to the reaction mixture. After 1 hour, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified via flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give methyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidine-1-carboxylate (93 mg, 0.23 mmol, 79% yield) as a white solid. ESI-MS (M+1): 404 calc. for C23H25N5O2 403.
Reaction SMILES: Cl[CH:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([Br:16])[CH:10]=2)=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][NH:3]1.[OH-:21].[K+]>C(O)(C)(C)C>[Br:16][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([Br:15])[CH:12]=1)[O:8][C:7]1[C:2](=[O:21])[NH:3][CH:4]=[CH:5][C:6]=1[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)C1=C(Oc2cc(Br)cc(Br)c2)C(Cl)NC=C1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-chloro-3-(3,5-dibromophenoxy)-4-(trifluoromethyl)-1,2-dihydropyridine (1.64 g, 3.80 mmol) and potassium hydroxide (0.640 g, 11.4 mmol) were dissolved in tert-butanol in a round bottom flask and placed in an oil bath at 75° C. under N2. After 16 hours, the reaction mixture was allowed to cool to room temperature and quenched with saturated aqueous ammonium chloride (25 mL). This mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give the title compound as a white solid. 1H NMR (DMSO-d6) δ 12.68 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.24-7.22 (m, 2H), 6.47 (d, J=Hz, 1H). LRMS (M+1)=413.5.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH4+:10].[OH-]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH2:10])=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)Cc1cccs1
Yield: 64 %

Procedure:
To a mixture of concentrated NH4OH (100 mL) and ice was added 2-thiopheneacetyl chloride (13.0 g, 80.9 mmol). The desired compound crystallized from the reaction mixture. Recrystallization from hot water gave 2-thiopheneacetamide (8.08 g, 64% yield) as white crystals. mp 146°-147° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:39][C:40]3[CH:45]=[C:44]([CH3:46])[C:43]([O:47]CC4C=CC=CC=4)=[C:42]([CH3:55])[CH:41]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:56]=[CH:57][CH:58]=[CH:59][C:4]=2[NH:3]1.[H][H]>CCO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:39][C:40]3[CH:45]=[C:44]([CH3:46])[C:43]([OH:47])=[C:42]([CH3:55])[CH:41]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:56]=[CH:57][CH:58]=[CH:59][C:4]=2[NH:3]1
Reactant: CCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
2.00 g (2.47 mmol) of (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 25 mL EtOH were combined with 200 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen until the reaction came to an end. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i.vac. The residue was reacted further without any purification by chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8](Br)[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([C:21]4[CH:20]=[C:19]([CH3:28])[CH:24]=[CH:23][CH:22]=4)[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(N)ccc4c3c2)c1
Temperature: 100 °C

Procedure:
7-Amino-3-bromo-9H-carbazole-1-carboxamide 470B (350 mg, 1.151 mmol), m-tolylboronic acid (313 mg, 2.302 mmol), PdCl2(dppf)-CH2Cl2 adduct (94 mg, 0.115 mmol), and Na2CO3 (2M) (2.88 mL, 5.75 mmol) were mixed with DME (15 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 100° C. in an oil bath for 4 hrs. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 316.04 (M+H)+. 1H NMR (DMSO-d6) δ ppm 10.89 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.82 (d, 1H, J=8.2), 7.67 (s, 1H), 7.63 (d, 1H, J=7.6), 7.41(s, 1H), 7.36 (t, 1H, J=7.6), 7.14 (d, 1H, J=7.6), 6.81 (s, 1H), 6.5 (d, 1H, J=8.3), 5.24 (bs, 2H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:18]([O:20]CC)=[CH2:19])[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4]>C1COCC1.Cl>[C:18]([C:7]1[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=1)(=[O:20])[CH3:19]
Reactant: C=C(OCC)c1nc(C(=O)OC)cn1COCC[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)=O)n1
Reaction time: 3 h

Procedure:
Into a flask containing a solution of methyl-2-(1-ethoxyvinyl)-1-((2-(tri-methylsilyl)-ethoxy)methyl)-1H-imidazole-4-carboxylate (3.5 g, 10.7 mmol) in THF (25 ml), 2 N HCl (25 ml) was added at RT and stirred for 3 h. The reaction mixture was concentrated and extracted with DCM. The organic layer was evaporated and the residue was purified by flash chromatography. Yield 2.6 g. 1H-NMR (400 MHz; CDCl3): δ −0.016 (s, 9H), 0.94 (t, 2H), 2.73 (s, 3H), 3.58 (t, 2H), 3.94 (s, 3H), 5.76 (s, 2H), 7.93 (s, 1H).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.Cl.O.C(OCC)(=O)C>O1CCCC1>[C:10]1([CH:7]2[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC=C1CCC(c2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution in tetrahydrofuran (10.0 mL) of the compound (3.59 g) obtained in step (1) above, 3 mol/L hydrochloric acid was added and the mixture was refluxed for 4 hours. After cooling the reaction mixture to room temperature, water was added to it and three extractions were conducted with ethyl acetate. The combined organic layers were washed with water and then concentrated under reduced pressure to give the titled compound as a colorless oil (2.75 g).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:8].N1CCC=CCC1=O.[H-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.O>[CH2:30]([N:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: O=C1C=CCCCN1
Reactant: CCCCCCCCCCCCBr
Agent: O=C1CC=CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCN1CCCC=CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.4 g (0.102 mol) of a mixture of azacyclohept-3-ene-2-one and azacyclohept-4-ene-2-one in THF was added dropwise to a suspension of 4.8 g (107 mmol) of sodium hydride (50% oil dispersion) in THF. The mixture was stirred at room temperature for 1 hour, 25.4 g (0.102 mol) of dodecyl bromide was added, and the solution was refluxed for 5 hours. The mixture was cooled, water was added, and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with water, the organic phase dried over MgSO4 and concentrated in vacuo to yield an oil which was Kugelrohr distilled to give 15.5 g of crude product. This material was subjected to flash chromatography (silica gel; 9:1 petroleum ether/ether V/V) to give 1-dodecylazacyclohept-3-ene-2-one, Rf =0.5, GC (column: 48 inch, 2% OV 101; conditions: injector, detector 320° C., program; 140° C. for 3 min, then to 190° C. in 30° C./min) GC retention time, 7.74 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:27][CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:25][CH3:26])(=[O:30])[CH3:29]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a solution of 1-[9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (122.0 mg, 0.300 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from methanol/n-hexane to give the title compound as a colorless powder (94.7 mg, 0.211 mmol, 70%).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([CH2:14][CH2:15][NH2:16])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>C(O)(=O)C>[C:1]1(=[O:6])[N:16]([CH2:15][CH2:14][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: NCCCCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of maleic anhydride (0.05 mole) in acetic acid (20 mL) was mixed with a solution of ε-Amino-n-caproic acid (0.05 mole) in acetic acid (50 mL) and stirred at room temperature for 2 hours. An additional amount of acetic acid (150 mL) was added and the reaction mixture refluxed for 16 hours. The reaction mixture was evaporated under vacuo to an oil and chloroform was then added (50 mL). The solution was left to stand for 16 hours at room temperature whereupon impurities were precipitated out of the solution. The precipitate was filtered and the filtrate was collected, evaporated under vacuo and chromatographed on silica gel using chloroform:acetic acid (95:5) to give 6-Maleimidocaproic acid 23 (8 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:28])=[C:18]([CH:24]=[C:25]([CH3:27])[CH3:26])[CH:19]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)cc2C=C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=Cc1cc(C)ccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
2-[4-Methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (764 mg, 2.02 mmol) is dissolved in EtOH (25 mL), and solid KOH (2.32 g, 40 mmol) and water (2.5 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in a mixture of water (40 mL) and EtOAc (20 mL) and the organic layer is separated. The aqueous layer is adjusted to approximately pH 7 with conc. HCl then extracted with EtOAc (2×15 mL). The combined organic layers are concentrated in vacuo to yield product (279) as off-white solid (544 mg, 78%).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)[CH:9]=[CH:10][C:4]=2[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN1CCCC1=O>[C:21]1([NH:20][C:2]2[NH:6][C:5]3[CH:7]=[C:8]([B:11]4[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]4)[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2ccc3nc(Cl)[nH]c3c2)OC1(C)C
Reactant: Nc1ccccc1
Solvent: CN1CCCC1=O
Product: CC1(C)OB(c2ccc3nc(Nc4ccccc4)[nH]c3c2)OC1(C)C
Temperature: 140 °C

Procedure:
2-Chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (200 mg, 0.718 mmol) and aniline (669 mg, 7.18 mmol) were mixed in N-methyl-2-pyrrolidinone (2 mL). The solution was heated at 140° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated to give the title compound, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[Cl:20][C:4]1[CH:3]=[C:2]([NH:24][CH:21]2[CH2:23][CH2:22]2)[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=1
Reactant: NC1CC1
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(Cl)cc(NC3CC3)n2n1)c1cccnc1
Yield: 47.5 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and cyclopropylamine (113 μL; 1.62 mmol; 5.00 eq) to give the title compound as a white solid (50 mg, 43%). HPLC, Rt: 2.59 min. (purity 92.6%). LC/MS, M+(ESI): 328.8, M−(ESI): 326.9.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH3:34][N:35]([CH3:41])[S:36]([CH:39]=[CH2:40])(=[O:38])=[O:37]>>[CH3:34][N:35]([CH3:41])[S:36]([CH2:39][CH2:40][N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)(=[O:38])=[O:37]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: C=CS(=O)(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(=O)(=O)N(C)C)C3)ccc1-2
Yield: 75 %

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and ethenesulfonic acid dimethylamide were reacted. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 2% MeOH in DCM) to give 443 as a beige solid (117 mg, 75%). LCMS: RT=7.69 min, [M+H]+=503. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=8.17 Hz), 7.89 (1H, s), 7.08 (1H, dd, J=8.21, 1.86 Hz), 6.99-6.96 (1H, m), 5.92-5.83 (1H, m), 4.38 (2H, t, J=5.05 Hz), 3.77 (2H, t, J=6.90 Hz), 3.74-3.64 (1H, m), 3.39 (2H, t, J=5.06 Hz), 3.23 (2H, t, J=6.67 Hz), 3.00-2.92 (4H, m), 2.87 (6H, s), 1.60 (6H, d, J=6.64 Hz)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([CH2:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1CCC=CC=1.[C:26]1([CH3:32])[CH:31]=[CH:30]C=[CH:28][CH:27]=1>>[CH:17]12[CH2:30][CH2:31][CH:26]([CH:27]=[CH:28]1)[CH2:32][CH:16]2[S:13]([CH2:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:18][CH3:19])[C:2]([Br:1])=[CH:11][CH:10]=1)(=[O:15])=[O:14]
Reactant: Cc1ccccc1
Reactant: C=CS(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Solvent: C1=CCCC=C1
Product: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(Br)c1OC
Temperature: 125 °C

Procedure:
A solution of methyl 3-bromo-2-methoxy-6-(vinylsulphonylmethyl)benzoate (Intermediate 172, 0.5 g), and cyclohexadiene (0.343 g) in toluene (0.5 ml) was sealed in a vial and heated at 125° C. for 3 days. After cooling, the mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-40% to give methyl 6-(bicyclo[2.2.2]oct-5-ene-2-ylsulphonylmethyl)-3-bromo-2-methoxybenzoate (0.455 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([OH:15])[CH2:13][CH2:12][CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:12][CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)C(NC(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCC(OS(C)(=O)=O)C(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of Racemate-ethyl 3-(tert-butoxycarbonylamino)-4-hydroxycyclohexanecarboxylate (12.0 g, 42 mmol) and triethylamine (12.7 g, 126 mmol) in dichloromethane (150 mL) was added methanesulfonyl chloride (9.5 g, 84 mmol) dropwise at 0° C., and the mixture was stirred at 0° C. for 3 hours. The solution was washed with water (100 mL×3) and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (15 g, crude) as a yellow oil. MS (ES+) C15H27NO7S requires: 365, found: 266 [M+H−100]+.
Reaction SMILES: Cl[Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C1(NC2CCCCC2)CCCCC1.Cl[SiH3].Cl.[OH:28][CH2:29][CH:30]([CH2:32][OH:33])[OH:31]>>[CH2:4]([O:3][Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:28][CH2:29][CH:30]([CH2:32][OH:33])[OH:31])[CH3:5]
Reactant: OCC(O)CO
Reactant: CCO[Si](Cl)(OCC)OCC
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: [SiH3]Cl
Product: CCO[Si](OCC)(OCC)OCC(O)CO
Yield: 90 %

Procedure:
Glycerol (GL) was reacted with chlorotriethoxysilane (CTS) in a 1:1 ratio at 0° C. in a 50/50 mixture of ethanol/cyclomethicone, using a 1:1 ratio of dicyclohexylamine to chlorosilane as the HCl scavenger. The resulting product, 1-triethoxysilylglycerol, was obtained in 90% yield and was dissolved to a 10% by weight solution in a 50/50 by volume mixture of ethanol/cyclomethicone.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]=O)=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18].[BH4-].[Na+]>CO>[OH:1][C:2]1[C:3]([CH2:12][NH:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH2:17][OH:18])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: O=Cc1cc2c(cc1O)CCCO2
Reactant: Nc1ccccc1CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccccc1NCc1cc2c(cc1O)CCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-7-carboxaldehyde (400 mg, 2.27 mmol) and o-aminobenzylalcohol 282 mg, 2.25 mmol) in methanol (30 mL) was brought to a gentle boil and the volume slowly concentrated to 10 mL. An additional portion of methanol (20 mL) was added and the above process repeated two times. The mixture was cooled (ice bath) and a few drops of water added to aid in the crystallization of the Schiff's base. This material (440 mg) was collected by filtration, redissolved in methanol (30 mL) and sodium borohydride (60 mg, 1.59 mmol) was added in portions. The color was discharged immediately and the mixture allowed to stir at room temperature for 10 minutes. The reaction mixture as concentrated to half its original volume then poured into water (35 mL). After acidification (pH=5) with 2N HCl the mixture was filtered, and the filtrate basified with 7% NaHCO3. The product, which precipitated, was collected by filtration and vacuum dried to afford 6-hydroxy-7-(2-hydroxymethylphenyl)aminomethyl-3,4-dihydrobenzopyran (300 mg, 46.8%), m.p. 141-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21].CC1NC=CN=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: CC(C)[C@H](NCc1ccc(Cl)cc1)C(=O)O
Agent: Cc1ncc[nH]1
Product: CCCCC(=O)N(Cc1ccc(Cl)cc1)[C@H](C(=O)O)C(C)C
Yield: 77.7 %

Procedure:
In a manner similar to Example 5 and starting from 15 g (62 mmol) of N-(4-chlorobenzyl)-L-Valine, 12 mL (99 mmol) of valeryl chloride and 7.7 g (93 mmol) of 2-methylimidazole, 15.7 g (77%) of N-(4-chlorobenzyl)-N-valeryl-L-Valine is obtained. The solid is recrystallised from a mixture of EtOH:H2O 1:1.