Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1.C(OCC)C>C(Cl)Cl.Cl>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1
Temperature: 56 °C
Yield: 21.1 %

Procedure:
[2-(Methylsulfonyl)ethyl]amine (267 mg, 2.169 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (100 mg, 0.217 mmol) were combined and heated to 56° C. overnight. The reaction mixture was cooled to rt and diluted with DCM and 10% aqueous HCl. The layers were separated and the water layer was extracted twice more with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to yield an oil. The oil was chromatographed on silica gel eluting with 100% DCM to 4:6 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were combined and concentrated to yield an oil. Diethyl ether was added to the oil and concentrated to obtain the title compound as a light brown solid (25.1 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6 heated to 60° C.) δ ppm 10.53-10.65 (m, 1H) 8.06-8.16 (m, 1H) 7.88 (s, 1H) 7.30-7.42 (m, 1H) 7.16-7.30 (m, 4H) 7.05 (d, J=3.6 Hz, 1H) 6.53-6.65 (m, 1H) 6.14-6.27 (m, 1H) 3.59-3.74 (m, 2H) 3.24-3.43 (m, 3H) 2.97 (br. s., 3H) 1.36 (dd, J=6.6, 2.7 Hz, 6H). MS (ESI): 548.0[M+H]+.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][NH:10][CH3:11])[N:8]=1)([CH3:3])[CH3:2].O([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])C1C=CC=CC=1.[C:29]1(C)C=CC=CC=1.CCCCCCC>CCOC(C)=O>[CH3:29][O:28][C:26](=[O:27])[C@H:22]([CH:23]([CH3:24])[CH3:25])[NH:21][C:19]([N:10]([CH3:11])[CH2:9][C:7]1[N:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:5][CH:6]=1)=[O:20]
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: Cc1ccccc1
Reactant: CNCc1csc(C(C)C)n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Temperature: 110 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
Into a 500 ml 3-neck round bottom flask equipped with mechanical stirrer, nitrogen atmosphere, thermocouple, heating mantle and condensor was charged the product of Example 73B (28.1 g, 0.165 mols), phenoxycarbonyl-(L)-valine (41.5 g, 0.165 mol) and 155 ml toluene. This solution was warmed to reflux (110° C.) and stirred for three hours, then cooled to 20°±5° C. and washed with 2×69 ml 10% citric acid followed by 1×69 ml water, 1×116 mls 4% sodium hydroxide, 1×58 ml 4% sodium hydroxide and finally 1×58 ml water. The organic product solution was then treated with 3 grams of activated carbon at reflux for 15 minutes, filtered through infusorial earth to remove carbon, and the carbon/infusorial earth cake was washed with 25 ml hot toluene. Next the solvent was removed to afford a brown oil which solidifed upon cooling. This brown solid was dissolved with warming in 31 ml EtOAc and 257 ml heptane at 60°±5° C. This solution was slowly cooled to 25° C., stirred 12 hours, cooled further to 0° C., and stirred 3 hours. The crystals were collected by filtration and washed with 50 ml 1:9 EtOAc/Heptane. The solid was dried in a 50° C. vacuum oven for 12 hours to afford 41.5 grams of the desired product as a tan-colored solid (76.9%).
Reaction SMILES: [CH3:1][N:2]([O:23][CH3:24])[C:3](=[O:22])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]([O:23][CH3:24])[C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH3:27])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CON(C)C(=O)c1cc(O)ccc1NC(=O)OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)OCc2ccccc2)c(C(=O)N(C)OC)c1
Temperature: 0 °C

Procedure:
An N,N-dimethylformamide (8 ml) solution of N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide (0.8 g), methyl iodide (0.2 g) and potassium carbonate (0.5 g) was stirred for 3 hours at 60° C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The organic layer was washed with water, which was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give N-methyl-N-methyloxy 2-benzyloxycarbonylamino-5-methyloxy-benzamide as a yellow oily product (0.55 g).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[CH3:23]/[C:24](=[CH:27]\[CH3:28])/[CH2:25]O>>[CH:10]([N:8]1[CH2:9][CH:6]([O:5][CH2:23]/[C:24](/[CH3:25])=[CH:27]/[CH3:28])[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C/C=C(\C)CO
Product: C/C=C(\C)COC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 1-benzhydrylazetidin-3-yl methanesulfonate (447 mg, 1.41 mmol) in (E)-2-methylbut-2-en-1-ol (1.2 g, 14.1 mmol) was stirred under microwaves at 110° C. for 30 minutes. After concentration to dryness, the residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as eluent. The title product was obtained as a colorless oil (290 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][N:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[CH:24]=[N:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Br)cn1
Product: COc1cc(-c2ccc(C(F)(F)F)nc2)ccn1
Yield: 816.4 %

Procedure:
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.24 g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g, 11 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (1.1 g, 81%) as a white solid: ESI MS m/z 255 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([OH:18])=O)[C:6](=[O:15])[N:7]2[CH:12]([CH3:14])[CH3:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH2:30]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH2:41])[CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]>ClCCl.Cl>[ClH:1].[CH2:30]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH:41][C:16]([C:5]2[C:6](=[O:15])[N:7]([CH:12]([CH3:13])[CH3:14])[C:8]3[C:3]([CH:4]=2)=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=3)=[O:18])[CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN1CCC(CN)CC1
Reactant: CC(C)n1c(=O)c(C(=O)O)cc2c(Cl)cccc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCN1CCC(CNC(=O)c2cc3c(Cl)cccc3n(C(C)C)c2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 117.1 %

Procedure:
To a solution of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.376 mmol, step 4) in dichloromethane (1 mL) was added oxalyl chloride (0.10 mL, 1.13 mmol) and a drop of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 1.5 h. The solvent and excess amount of oxalyl chloride was removed in vacuo. The residue was dissolved in dichloromethane (1 mL) and [(1-butylpiperidin-4-yl)methyl]amine (128 mg, 0.753 mmol) in dichloromethane (1 mL) was added at 0° C. and the mixture was stirred at room temperature for 1 h. Then, the mixture was quenched with water (10 mL) and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layer was dried over sodium sulfate and concentrated in vacuo gave a colorless oil. The resultant oil was dissolved in 10% methanolic hydrogen chloride (5 mL) and stirred for 16 h. The formed precipitate was filtrated and washed with methanol to give 100 mg (59%) of the title compound as a white solid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C(=O)=O.C[O:21][C:22]([C:24]1[C:25]([CH2:40][CH2:41][O:42][CH3:43])=[N:26][C:27]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)=[N:28][CH:29]=1)=O.C(OC(C1C(CCOC)=NC(C2C=NC(C(F)(F)F)=CC=2)=NC=1)=O)C>C1COCC1>[CH3:43][O:42][CH2:41][CH2:40][C:25]1[C:24]([CH2:22][OH:21])=[CH:29][N:28]=[C:27]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=2)[N:26]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Agent: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)nc2)nc1CCOC
Agent: O=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 1.2 M solution of DIBALH in toluene (50 ml, 60 mmol) was dropped within 20 min to a dry ice cooled (−30° C.) solution of 4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid methyl ester and 4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid ethyl ester (6.83 g, 20 mmol) in THF (100 ml). The reaction mixture was warmed to 0° C., stirred for 1 h at this temperature, the cooling bath was removed and stirring was continued for 1 h at ambient temperature. The mixture was cooled to 0° C., neutralized with aqueous KHSO4 solution (10%) and extracted three times with ether. The combined extracts were washed with aqueous NaCl solution (10%), dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was crystallized (dichloromethane/ether, 0° C.) to give 6.72 g (21.4 mmol, quant.) [4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl) -pyrimidin-5-yl]-methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[CH:5]=1)([O-])=O>C(O)C.O1CCCC1.[C].[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)[CH:5]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Yield: 65.2 %

Procedure:
To a mixture of 2.81 g of ethyl 4-nitro-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 26 in 50 ml of ethanol-tetrahydrofuran (1:1) was added 0.5 g of palladium-carbon. Catalytic reduction was performed at room temperature under normal pressure until absorption of hydrogen was discontinued. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with isopropyl alcohol to obtain 1.72 g of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:14][CH2:15][CH2:16][CH2:17][O:7][C:3]1[CH:2]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: BrCCCOc1cccc(-c2ccccc2)c1
Reaction time: 24 h
Yield: 57.9 %

Procedure:
To a solution of 3-biphenylol (0.0574 g, 0.337 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.340 mL, 3.35 mmol) followed by Cs2CO3 (0.172 g, 0.529 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0568 g, 57.8%). EI-MS Rt (2.59 min).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[S:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[K+].C>C(O)CO.CO>[CH3:21][C:18]1[S:17][C:16]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:22])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(C)s1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Temperature: 25 °C
Yield: 0.8 %

Procedure:
A suspension of N-[3-[(5-methyl-2-thienylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (93.8 g, 0.293 mole) was refluxed in ethylene glycol (500 ml) for 45 minutes. The solution was cooled and water (200 ml) and solid potassium hydroxide pellets (23.25 g, 0.41 mole) were added. The resulting solution was refluxed for one hour and then filtered hot into ice water (2 liters) and acidified with 3N hydrochloric acid to give a solid which was collected by filtration and dried to give 52.3 g of crude title compound (65% yield). A 2.0-g portion was dissolved in hot methanol, treated with charcoal, filtered while hot, and cooled to room temperature. Addition of water caused a precipitate to form which was collected by filtration and dried under high vacuum at room temperature overnight to give 0.68 g of title compound, mp >250° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:74][C@@H:75]1[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:74][C@@H:75]4[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76]4)=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (67 mg, 0.13 mmol), PyBOP® (37 mg, 0.072 mmol), DIEA (23 μL, 0.13 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (16 mg, 0.084 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalent of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo to afford the crude (3R)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1
Reactant: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(S(C)(=O)=O)C4)CC2)no1
Reaction time: 16 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.100 g, 0.24 mmol) and triethylamine (0.70 ml, 0.50 mmol) in dichloromethane (4.8 ml) was added methanesulfonyl chloride (0.020 ml, 0.26 mmol) at room temperature. After stirring for 16 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.053 g, 48%) as white solid. MS m/e: 463 ([M+H]+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[I:19]I.O>C1COCC1>[I:19][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1
Reactant: II
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(I)ccc2c1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 92 mL, 230 mmol) is added via dropping funnel to a solution of 2-bromo-6-methoxy-naphthalene (49.5 g, 209 mmol) in anhydrous THF (2 L) at −75° C. at such a rate that the temperature is kept below −70° C. (over 45 min). The resulting yellow solution is stirred for 15 min at −75° C. A solution of iodine (58.3 g, 230 mmol) in anhydrous THF (100 mL) is added via a fresh dropping funnel until the red iodine colour persists (addition over 45 min, max. temp. −68° C.). The mixture is warmed to rt. and water (1.3 L) is added. The mixture is extracted with dichloromethane (2 L) with brine (500 mL) being added to aid the separation. The aqueous fraction is back-extracted with dichloromethane (1 L). The combined organic fractions are reduced in vacuo to approx. 1 L, washed with saturated aqueous sodium metabisulphite (100 mL), then brine (200 mL), dried (Na2SO4), filtered and solvent removed in vacuo. The crude residue is recrystalised from IMS (1.9 l) washing with ice-cold IMS (2×150 mL) and dried in a vacuum oven at 70, ° C. to give a light cream crystalline solid. 46.45 g, 78%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]3[CH:21]=[C:22](C(OCC)=O)[N:23]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1)=[O:2].Br[CH2:30][C:31](=O)CC>>[CH2:30]([C:22]1[N:23]=[C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][N:12]2[CH:21]=1)[CH3:31]
Reactant: CCOC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: CCC(=O)CBr
Product: CCc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1

Procedure:
This compound was prepared in a manner according to ethyl 7-(4-formylphenyl)-6-phenylimidazo[1,2-a]pyrimidine-2-carboxylate by using 1-bromobutan-2-one instead of ethyl 3-bromo-2-oxopropanoate in step 5.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[CH2:45][C:46]([F:49])([F:48])[F:47])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(CN(CC(F)(F)F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (92 mg) in DMF (0.89 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (77 μL) and potassium carbonate (74 mg) at 0° C., and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was cooled to 0° C., potassium carbonate (246 mg) was added, and the mixture was stirred at 80° C. for 2 days. The reaction mixture was cooled to 0° C., 2,2,2-trifluoroethyl trifluoromethanesulfonate (256 μL) was added, and the mixture was further stirred at 80° C. for 3 days. The mixture was cooled to room temperature, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was directly used for the next reaction.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1COCC1>[C:1]1([N:7]2[C:8](=[O:9])[NH:10][C:12](=[O:13])[S:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: O=C(Cl)SCl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(-c2ccccc2)s1
Yield: 13.8 %

Procedure:
To the solution of phenyl-urea (13.0 g, 95.48 mol) in THF (100 mL) was slowly added chlorocarbonyl sulfenylchloride (13 mL, 148.85 mmol) at RT. The reaction mixture was refluxed overnight, the volatiles removed in vacuo yielded 2-phenyl-1,2,4-thiadiazolidine-3,5-dione as a white solid (4.0 g, 20%). 1H NMR (DMSO-d6): δ 12.49 (s, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.27 (t, J=7.2 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH2:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:3]([OH:11])[CH2:2][CH2:12][CH3:13].[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Reactant: c1ccc(CC2CCNCC2)cc1
Product: CCCCO
Product: Cn1nc(N2CCC(Cc3ccccc3)CC2)c(=O)n(C)c1=O
Yield: 93 %

Procedure:
The compound 10 (oil) is prepared from the triazine 1b and from 4-benzyl-piperidine according to the synthesis method 1 in n-butanol (yield: 93%).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[N:31][CH:32]=1)=O.[I:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[I:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][CH2:15][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[N:31][CH:32]=2)=[CH:46][CH:45]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(I)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (2.2 g, 10.1 mmol) was added to a DCE solution (22 mL) of ethyl 3-(5-(2-formyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (2.0 g, 5.1 mmol), 4-iodoaniline (1.2 g, 5.6 mmol), and AcOH (1.2 mL, 20.3 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.