Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH2:31][CH2:32][CH3:33]>>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:31][CH2:32][CH3:33])[CH:20]=2)[O:17][CH:18]=1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Reactant: CCCBr
Product: CCCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 272 and 1-bromopropane, white powdery 1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-propoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[C:17]2=[O:31])[CH2:10][CH2:9]1)=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:54][C:55]1[C:70]([OH:71])=[CH:69][CH:68]=[CH:67][C:56]=1[C:57]([NH:59][C:60]1[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][N:61]=1)=[O:58]>CN(C)C=O.O.C(N(CC)CC)C>[Cl:66][C:63]1[CH:64]=[CH:65][C:60]([NH:59][C:57](=[O:58])[C:56]2[CH:67]=[CH:68][CH:69]=[C:70]([OH:71])[C:55]=2[NH:54][C:26](=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([C:18]3[C:17](=[O:31])[N:16]([CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:21]=[CH:20][CH:19]=3)=[CH:30][CH:29]=2)=[N:61][CH:62]=1
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cccc(-c3ccc(C(=O)O)cc3)c2=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2cccn(CCN3CCNCC3)c2=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.8 %

Procedure:
4-(1-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-2-oxo-1,2-dihydropyridin-3-yl)benzoic acid (731 mg) was dissolved in N,N-dimethylformamide (15 mL), 1-hydroxybenzotriazole (253 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (359 mg) and triethylamine (261 μL) were added, and 2-amino-N-(5-chloro-2-pyridinyl)-3-hydroxybenzamide (412 mg) was added, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, and the precipitate formed was collected by filtration and washed with water. The resulting solid was dried under reduced pressure and dissolved in tetrahydrofuran (15 mL), and acetic acid (448 μL) was added, followed by stirring at 60° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and then azeotroped twice with toluene. The residue was purified by NH-silica gel column chromatography (methanol/chloroform=0% to 5%). The resulting compound was dissolved in ethyl acetate (10 mL), and 4 N hydrochloric acid/ethyl acetate (3.88 mL) was added, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and aqueous saturated sodium hydrogencarbonate solution was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (methanol/chloroform=0% to 5%) to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazin-1-ylethyl)-1,2-dihydropyridin-3-yl]benzoyl}amino)benzamide (867 mg) as a yellow white solid.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[O:11][C:10]([CH3:20])([CH3:19])[CH2:9]2.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:21])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:29](=[O:30])[C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=4)[CH:16]=3)[O:11][C:10]([CH3:19])([CH3:20])[CH2:9]2)[N:4]=1
Reactant: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(N)ccc2O1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(NC(=O)c3ccc(Cl)cn3)ccc2O1
Yield: 85 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,2-dimethyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazine]-2′,6-diamine (intermediate B7.3) and 5-chloropicolinic acid yielded the title compound (85% yield) as a white solid. MS (ISP): m/z=437.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](N(OC)C)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][C:18]=1[F:25].[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([F:25])[CH:19]=1)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Reactant: Fc1cc([Mg]Br)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 60 (15.12 g, 64.79 mmol) and THF (50 mL) cooled to 0° C. was added dropwise (4-chloro-3-fluorophenyl)magnesium bromide (226.8 mL, 113.4 mmol) and the solution was stirred at 0° C. for 2 h. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane to afford 18.36 g (93.6%) of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(Cl)Cl.O.[Cl:24][S:25](O)(=[O:27])=[O:26]>>[Cl:18][C:15]1[CH:14]=[C:13]([F:19])[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[N:5]([CH3:11])[N:4]=2)=[CH:17][C:16]=1[S:25]([Cl:24])(=[O:27])=[O:26]
Reactant: Cn1nc(-c2ccc(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: O
Product: Cn1nc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 4-chloro-3-(4-chloro-2-fluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 20 mL of chlorosulfonic acid was heated in a 120° C. oil bath for four hours and allowed to cool to room temperature. Methylene chloride was added and the solution added dropwise to a stirring mixture of ice and water (caution, extremely reactive). The layers were separated and the aqueous layer was washed with methylene chloride. The combined organic layers were dried with MgSO4, filtered and concentrated and the resultant solid residue washed with a very small amount of ether and recrystallized from hexanes to afford 1.65 g (63%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenesulfonyl chloride as a white solid; mp 116°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13](=[O:16])[CH:14]=[CH2:15])=[CH:7][CH:6]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:20][CH2:19]1>CCO>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15][N:18]2[CH2:19][CH2:20][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:22][CH2:23]2)=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: C=CC(=O)CNc1ccc(CC(=O)OC)cc1
Solvent: CCO
Product: COC(=O)Cc1ccc(NCC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Yield: 71.2 %

Procedure:
A stirred solution of [4-(acryloylmethylamino)phenyl]acetic acid methyl ester (˜22.3 mmol) and biphenyl-2-ylcarbamic acid piperidin-4-yl ester (6.61 g, 22.3 mmol) in EtOH (15.0 mL) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give the title compound (8.41 g, 71% yield, 2 steps) as a brown sticky solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][C:3]=1[CH3:13].CN([CH:17]=[O:18])C>CCCCCC.C1COCC1>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:17]=[O:18])=[C:3]([CH3:13])[N:4]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(Cl)c2ccccc2c1Br
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c2ccccc2c1C=O
Reaction time: 0.67 h
Yield: 81 %

Procedure:
n-BiLi (12.3 ml of 1.6 M in hexane, 20 mmol) is added dropwise to a solution of 4-bromo-1-chloro-3-methyl-isoquinoline (4.6 g, 18 mmol) in THF (80 ml) at −78° C. and the mixture is stirred for 40 min. DMF (4.2 ml, 54 mmol) is then added slowly. The cold bath is removed, and stirring is continued for 15 min. The mixture is acidified with 1N—HCl to pH 2 and extracted with ether. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel to give 3.0 g of 1-chloro-3-methyl-isoquinoline-4-carbaldehyde. 1H NMR (CDCl3) 10.9 (s, 1H), 9.06 (d, 1H), 8.40 (d, 1H), 7.88 (t, 1H), 7.70 (t, 1H), 2.99 (s, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>O1CCCC1>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[C:15]=1[O:20][CH3:21]
Reactant: COc1ccccc1OC
Reactant: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(CCCCCCBr)c1OC
Yield: 32 %

Procedure:
A solution of 1.55M butyl lithium in hexane (195mL, 0.3 mol) was added dropwise over 30 minutes to a stirred solution of 1,2-dimethoxybenzene (41.4g, 0.3 mol) in 700 mL of anhydrous tetrahydrofuran at room temperature under argon. The reaction mixture was stirred and heated at 40° for 4 hours and then cooled to -70°. A solution of 46 mL (0.3 mol) of 1,6-dibromohexane in 250 mL of anhydrous tetrahydrofuran was added dropwise over 30 minutes. The cooling bath was removed and the reaction mixture was stirred for 1 hour and then heated at 40° for 4 hours. Most of the solvent was removed, 90mL of 3NHCl was added and the product was extracted with hexane. The extract was washed with sodium bicarbonate solution, dried and concentrated under reduced pressure to yield an oil. Distillation gave 1-(6-bromohexyl)-2,3-dimethoxybenzene as a yellow oil (29 g, 32% yield, b.p 125°-140°/0.15 mm).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([C:9]2[O:13][CH:12]=[N:11][CH:10]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.[C:16]([C:18]1[N:19]=[CH:20][S:21][CH:22]=1)#[CH:17]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][O:14][C:4]1[CH:3]=[C:2]2[C:7]([CH:17]=[C:16]([C:18]3[N:19]=[CH:20][S:21][CH:22]=3)[NH:1]2)=[CH:6][C:5]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1
Reactant: COc1cc(N)c(I)cc1-c1cnco1
Reactant: C#Cc1cscn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: COc1cc2[nH]c(-c3cscn3)cc2cc1-c1cnco1
Temperature: 120 °C
Yield: 23.5 %

Procedure:
To a solution of 5-(4-amino-5-iodo-2-methoxyphenyl)oxazole (WO 0181340) (0.293 g, 0.93 mmol) in diethylamine (2.5 mL) was added 4-ethynylthiazole (0.118 g, 1.08 mmol) and bis(triphenylphosphine)palladiumdichloride (0.019 g, 0.027 mmol). The contents were purged with nitrogen and heated in a steel bomb at 120° C. for 20 minutes. The reaction mixture was cooled to rt and purified by silica gel column chromatography to provide the title compound (0.065 g, 20%). HPLC Ret. t=2.79 min. (A); LC/MS M+1=298.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2Cl)(=[O:16])=[O:15])=[O:12])[N:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)(=[O:16])=[O:15])=[O:12])[N:4]=1
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)C2CCCCC2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)C2=CCCCC2)n1
Yield: 52.7 %

Procedure:
36.2 g (0.1 mole) of N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-chlorocyclohex-1-ylsulfonamide (see Example 1) were suspended in 300 ml of methanol and 8 g (0.2 mole) of sodium hydroxide dissolved in 40 ml of water were added at room temperature. The reaction mixture was then stirred under reflux for 8 hours, evaporated in vacuo and taken up in 250 ml of water. After filtration and acidification with 2N HCl to pH 5, extraction was carried out with ethyl acetate and then the extracts were dried over sodium sulfate and evaporated. After adding n-hexane, 17.2 g (52.7% of theory) of N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-1-cyclohexenylsulfonamide were obtained, having a melting point of 163°-166° C.
Reaction SMILES: C(OC1C(C(C)C)CCC(C)C1)(=O)C1C(=CC=CC=1)[NH2:4].[C:21]([O-:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)O>>[CH:23]1[C:22]([C:21]([OH:30])=[O:29])=[CH:28][CH:27]=[C:26]([NH2:4])[CH:25]=1
Reactant: CC1CCC(C(C)C)C(OC(=O)c2ccccc2N)C1
Reactant: O=C([O-])c1ccccc1O
Product: Nc1ccc(C(=O)O)cc1

Procedure:
Menthyl Anthranilate or Salicylate
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]([CH2:32][CH2:33][O:34][CH3:35])=[C:30]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:30]([NH:29][CH2:32][CH2:33][O:34][CH3:35])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: COCCN=C=S
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1CC1CCOCC1
Yield: 65 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (70 mg) and 1-isothiocyanato-2-(methyloxy)ethane (50 mg) to give the title compound as beige solid (55 mg, 65%). LCMS (formate) Rt 0.68 min, MH+ 466
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:47]=1)[O:27][CH2:28][C:29]1[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O-].[Na+]>O1CCCC1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:47]=1)[O:27][CH2:28][C:29]1[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CC1(C)OB(/C=C2/c3ccc(F)cc3OCc3c(F)cccc32)OC1(C)C
Reactant: O=[N+]([O-])c1cc(Br)ccc1N[C@H]1C[C@H]2COCCN2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[O-]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cc(/C=C2/c3ccc(F)cc3OCc3c(F)cccc32)ccc1N[C@H]1C[C@H]2COCCN2C1
Temperature: 70 °C
Yield: 89.9 %

Procedure:
Degas three times a mixture of (4-bromo-2-nitro-phenyl)-((7S,8aS)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (0.011 mol, 4.0 g), (E)-3,7-difluoro-11-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-ylmethylene)-6,11-dihydro-dibenzo[b,e]oxepine (0.012 mol, 4.76 g), triphenylphosphine (0.0031 mol, 0.8 g) and sodium methoxide (0.03 mol, 1.6 g) in tetrahydrofuran/methanol (3:1) (120 mL) with nitrogen. Add palladium (II) acetate (1.0 mmol, 240 mg) to the reaction mixture and degas again three times with nitrogen. Heat the reaction mixture at 70° C. for 4 h. Cool the reaction mixture to room temperature, filter through a plug of diatomaceous earth and concentrate the filtrate under reduced pressure to obtain the title compound (5.0 g, crude).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:9][CH2:8][C:7]1[S:6][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(-c2ccncc2)sc1CO

Procedure:
To a solution of ethyl 4-methoxy-2-(4-pyridyl)-thiazole-5-carboxylate (169 mg, 0.639 mmol) in THF (4 mL) cooled in an ice-bath was added lithium aluminum hydride portionwise (48 mg, 1.26 mmol). After stirring for 15 minutes at ice temperature, excess LAH was destroyed by sequential addition of water (48 μL), 15% aqueous NaOH (48 μL), and water (144 μL). The mixture was diluted with THF, filtered through a pad of Celite, and evaporated. The title compound was purified by flash chromatography eluting with 25% acetone/hexane.
Reaction SMILES: C(OC([N:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:16])[C@@H:10]1[CH2:14][C@H:13]([Cl:15])[CH2:12][NH:11]1)=O)(C)(C)C.Cl.[CH2:22]([N:29]([C@@H:37]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:38]([OH:42])[C:39](O)=[O:40])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.P(C#N)(OCC)(OCC)=O>O1CCOCC1.CN(C)C=O.C(N(CC)CC)C>[CH2:22]([N:29]([C@@H:37]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:38]([OH:42])[C:39]([N:11]1[CH2:12][C@@H:13]([Cl:15])[CH2:14][C@H:10]1[C:9]([NH:8][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:16])=[O:40])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@H](Cl)CN1)C(C)(C)C
Reactant: O=C(O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 24 h
Yield: 88.9 %

Procedure:
12.2 g (0.04 mol) of (4S)-N-t-butoxycarbonyl-4-chloro-N-t-butyl-L-prolinamide were treated with 50 ml of a 4N solution of hydrogen chloride in dioxane, in order to remove the t-butoxycarbonyl group. The product thus obtained and 15.0 g (0.04 mol) of (2S,3S)-3-(N,N-dibenzylamino)-2-hydroxy-4-phenylbutyric acid were dissolved in 50 ml of dimethylformamide, and the solution was cooled with ice. 8.48 ml (52.0 mmol) of diethyl cyanophosphate, and then 11.2 ml (0.08 mmol) of triethylamine, were then added dropwise to the resulting mixture, which was then stirred for 1 day. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The diluted solution was washed with a 5% w/v aqueous solution of citric acid and with a 5% w/v aqueous solution of sodium hydrogencarbonate, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 20.0 g of the title compound as a colorless powder, melting at 64°-67° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:13]=[N:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21](=[O:32])[NH:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=3)[N:5]=2)[CH2:27][CH2:28]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc2ncc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
Sodium hydride (55% purity, 62 mg, 1.48 mmol, 1.5 eq) is added at room temperature to a stirred solution of 2-chloro-7-methoxy-quinoxaline (200 mg, 0.99 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), followed by [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (268 mg, 0.99 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated, and the residue is extracted with dichloromethane (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:1:0 to 0:9:1, v/v/v) to afford {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an orange solid (210 mg, 52% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1[NH:29][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[N:31][N:32]=1>>[CH2:22]([C:21]1[N:31]2[N:32]=[C:28]([CH3:27])[N:29]=[C:30]2[N:33]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: Cc1nnc(NC2CCOCC2)[nH]1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (1.2 g) and 5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.52 g, 66%).
Reaction SMILES: O(CCCC(O)=O)C1C=CC=CC=1.[N:14]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18][C:17]=2[S:16][C:15]=1[C:28]([OH:30])=O.[OH-].[Na+].[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[NH:36][CH3:37]>C1COCC1.O>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[N:36]([CH3:37])[C:28]([C:15]1[S:16][C:17]2[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[C:23]=2[N:14]=1)=[O:30]
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1nc2c(s1)CCOc1ccccc1-2
Agent: O=C(O)CCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1nc2c(s1)CCOc1ccccc1-2)c1ccccc1Cl

Procedure:
To a solution of 4-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (4.0 g, 12.4 mmol) in ethanol, was added ethyl thiooxamate (5.0 g, 37.4 mmol) and the reaction mixture was heated to reflux for 3 days. Purification on silica gave 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester, which was hydrolyzed to the carboxylic acid, 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid, in THF, sodium hydroxide, and water. 4,5-Dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid was coupled with 2-chloro-N-methylaniline using General Procedure B. Purification on silica gave 226. 1H NMR (400 MHz, CDCl3): 3.24 (2H, t), 3.37 (3H, s), 4.17-4.25 (2H, m), 6.74-6.79 (1H, m), 6.85 (1H, dd), 7.02-7.07 (1H, m), 7.11 (1H, dd), 7.27-7.33 (3H, m), 7.42-7.45 (1H, m). MS: (ESI+) MH 371