Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19](O)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([CH2:33][O:34][NH2:35])[CH2:32][CH2:31]1>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH:18]([OH:22])[C:19]([NH:35][O:34][CH2:33][CH:30]1[CH2:32][CH2:31]1)=[O:20])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: NOCC1CC1
Product: O=C(NOCC1CC1)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The reaction can be carried out in analogy to reaction step 20.3 by reacting 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-(cyclopropylmethyl)hydroxylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=[O:28])[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>O1CCCC1.C(Cl)Cl>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:18]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=[O:28])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CON(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2Cl)C1=O
Yield: 10.3 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 3.0 grams (0.012 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 1.8 grams (0.012 mole) of phthalic anhydride in 125 mL of tetrahydrofuran. The reaction mixture was dissolved in 200 mL of methylene chloride and washed with four 50 mL portions of an aqueous 10% hydrochloric acid solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a semi-solid residue. The residue was stirred and heated in ethyl acetate-heptane. The resultant solid was collected by filtration and was recrystallized from acetate/hexane to yield 0.5 gram of 2-[[2-chloro-4-[(2-carboxyphenyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 172° C., dec.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.Cl.Cl.[O:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:23][CH2:22][CH2:21]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CN(C=O)C>[O:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[N:30]2[CH2:35][CH2:34][N:33]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:32][CH2:31]2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5c4OCCC5)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A mixture of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (300 mg, 1.29 mmol) and 1-chroman-8-yl-piperazine bishydrochloride (395 mg, 1.36 mmol) were suspended in DCE (8 mL)/DMF (1 mL) and Et3N (0.54 mL, 3.88 mmol) was added. After about 10 min, NaBH(OAc)3 (356 mg, 1.68 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2 with 0.5% NH4OH) gave the title compound as a white foam (364 mg, 0.838 mmol, 65%). The foam was dissolved in THF/Et2O and 1 N HCl in Et2O (0.84 mL) was added. The resulting precipitate was collected by filtration, washed with Et2O and dried to give a white solid (368 mg). MS: APCI: M+1: 435.2 (Exact mass: 434.23).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=2[CH3:31])=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:25]3[CH:26]=[N:27][C:22]([O:21][C:20]4[CH:19]=[CH:18][C:17]([Cl:16])=[CH:33][CH:32]=4)=[C:23]([CH3:31])[CH:24]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1Oc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1ccc(Cl)cc1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (270 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (260 mg, 0.87 mmol, Amine-43, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([NH:22][C@H:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)[CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH2:40]([O:47][C:48]1[CH:49]=[CH:50][C:51]([Br:55])=[C:52](O)[CH:53]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:15]([O:19][C:20]([NH:22][C@H:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:31]=1)[CH2:24][O:25][C:50]1[CH:49]=[C:48]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:53]=[CH:52][C:51]=1[Br:55])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(OCc2ccccc2)cc1
Reactant: Oc1cc(OCc2ccccc2)ccc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(OCc2ccccc2)ccc1Br)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
Diisopropylazodicarboxylate (0.10 ml, 0.603 mmol) was added to (R)-2-(tert-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (161 mg, 0.469 mmol), 5-benzyloxy-2-bromophenol (131 mg, 0.469 mmol) and triphenylphosphine (160 mg, 0.610 mmol) in tetrahydrofuran (3 ml) under a nitrogen stream, followed by stirring for 5 hours at room temperature. Diisopropylazodicarboxylate (0.05 ml, 0.302 mmol) was added to the reaction mixture followed by stirring for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4, v/v) to give (R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (214 mg, Yield 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C:6]1([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)[CH3:2]>CCO.[Pd]>[CH2:31]([C:28]1[CH:29]=[CH:30][C:25]([S:22]([NH:21][C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:36])[CH2:10][CH2:9][NH:8][CH2:7]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCN(C(=O)OCc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CCNC2)cc1
Reaction time: 24 h
Yield: 62.5 %

Procedure:
A solution of benzyl 3-(2-ethoxy-2-oxoethyl)-3-(4-pentylphenylsulfonamido)-pyrrolidine-1-carboxylate (120 mg, 0.23 mmol) in EtOH (5 mL) was purged with nitrogen and Pd/C (25 mg) was added and the flask was purged with hydrogen and stirred for 24 h. The mixture was filtered through celite and concentrated. The residue was dissolved into H2O and lyophilized to give the title compound as a white solid (55 mg, 62%). MS ESI 383.2 [M+H]+, calcd for [C19H30N2O4S+H]+ 383.19.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1

Procedure:
Prepared from 2-indolinone and benzoic acid chloride
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:28][C:29](O)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:29](=[O:30])[CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)C(=O)CC2CCCCC2)CC1
Yield: 84.3 %

Procedure:
Using general procedure E, 4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.03 mmol) and cyclohexylacetic acid (161 mg, 1.13 mmol) afforded 4-[benzyl-(2-cyclohexyl-acetyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (360 mg, 85%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:21]([CH2:31][CH3:32])[CH:20]=1)=O.BrC(Br)=O>>[CH2:31]([C:21]1[CH:20]=[C:19]([CH2:17][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][CH2:11][C:5]=23)=[O:10])[CH:24]=[C:23]([CH3:25])[C:22]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:32]
Reactant: CCc1cc(C=O)cc(C)c1CCC(=O)O
Reactant: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Agent: O=C(Br)Br
Product: CCc1cc(CCC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc(C)c1CCC(=O)O

Procedure:
3-{2-Ethyl-4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-6-methyl-phenyl}-propionic acid is prepared from 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (Example R) and 3-(4-formyl-2-ethyl-6-methyl-phenyl)-propionic acid (Aldehyde 6) in analogy to Intermediate 2; LC-MS: tR=1.16 min, [M+1]=441.36; 1H NMR (CDCl3): δ 6.95 (s, 1H), 6.93 (s, 1H), 3.12-2.94 (m, 8H), 2.74 (q, J=7.6 Hz, 2H), 2.66 (q, J=7.6 Hz, 2H), 2.56-2.48 (m, 2H), 2.36 (s, 3H), 2.32 (s, 2H), 1.56 (t, J=7.0 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H), 1.24 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:12][CH:14]2[CH2:15][O:16]2)=[CH:7][CH:8]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-trifluromethyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C:16]([CH3:23])([CH3:22])[CH2:15]1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:37]=[O:38])[S:35][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[CH3:22][C:16]1([CH3:23])[CH2:15][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:32]4[CH:33]=[C:34]([CH:37]=[O:38])[S:35][CH:36]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][S:17]1(=[O:21])=[O:20]
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Reaction time: 0.08 h
Yield: 5.5 %

Procedure:
(racemic)-5-Bromo-3-(2,2-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (170 mg, 0.426 mmol) was placed in a microwave vial and dissolved in 1,4-dioxane (10 mL) and water (5 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (203 mg, 0.851 mmol) and K2CO3 (177 mg, 1.277 mmol) was added. Argon was bubbled through the mixture for 10 min. PdCl2(dppf) (16.43 mg, 0.034 mmol) was added, and argon was bubbled another 10 mins. The vial was sealed and put under microwave 5 mins at 100° C. with high absorption parameter. The mixture was run through a thiol-SPE column eluting with MeOH. The fraction containing product (lcms) are combined and solvent was evaporated. One fraction of the residue was purified by Preparative HPLC. Conditions: aqueous phase contains 0.1% NH4OH (Ammonium Gilson) starting with 20% acetonitrile to finish with 80% acetonitrile in 60 min. The product stays around 17-18 mins in the column. The title product (10 mg) was obtained. The other fraction was purified by FlashChromatography (DCM 100% to DCM 30%/-DCM 90/MeOH 7/NH4OH aq 3-70% in 30 mins) to give 90 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([CH3:24])=[C:8]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:16][CH2:15]3)[O:9]2)=[CH:4][CH:3]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:26]([O:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([CH3:24])=[C:8]([CH:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:18][CH2:19]3)[O:9]2)=[CH:4][CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCC(=O)N1CCC(c2oc3c(C=O)c(O)ccc3c(=O)c2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(c2oc3c(C=O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Yield: 96.4 %

Procedure:
A solution of 7-hydroxy-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carbaldehyde (250 mg, 0.73 mmol) obtained in Example 34-1, benzyl bromide (260 μL, 3.64 mmol), and potassium carbonate (503 mg, 3.64 mmol) in dimethylformamide (4 mL) was stirred at room temperature for 26 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained residue. Then, the supernatant was removed by decantation to obtain 305 mg of the title compound (yield: 97%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:8]=3[CH:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:8]=3[CH:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:18]=3)[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)c1cc(C(C)=O)ccc1-2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)Oc1cc(O)ccc1-2
Temperature: -78 °C

Procedure:
The mixture containing the compound from Step H (0.25 g, 0.565 mmol) was dissolved in CH2Cl2 (40 ml) and cooled to −78° C. and BBr3 in CH2Cl2 (1M, 11 ml) was added. The mixture was kept at −78° C. and allowed to warm to 15° C. overnight. The reaction was quenched with saturated NaHCO3 (5 ml) and extracted with CH2Cl2 (20 ml). The organic layer was washed with saturated NaHCO3, water and dried over Na2SO4. The solvent was removed and the crude product purified by preparative TLC plates. 1H-NMR (400 MHz, CDCl3) δH 1.55 (2H, m, NCH2CH2CH2), 1.80 (4H, m, NCH2CH2CH2), 2.56 (3H, s, COCH3), 2.81 (4H, m, NCH2CH2CH2), 3.01 (2H, m, NCH2CH2O), 4.22 (2H, m, NCH2CH2O), 6.13 (1H, s, Ph2CHO), 6.50 (1H, s, ArH), 6.60 (1H, d, ArH), 6.80 (2H, d, ArH), 7.21 (2H, d, ArH), 7.49 (1H, s, ArH), 7.65 (1H, d, ArH), 7.74 (1H, d, ArH), 7.97 (1H, d, ArH).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.[C:17]1([CH2:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:23]([NH:24][CH2:1][C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CNCc2ccccc2)COC1(C)C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A mixture of tert-butyl (4S)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.0 g, 4.36 mmol), phenylmethanamine (491 mg, 4.58 mmol) and toluene (8 mL) was heated under reflux with stirring for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in 1,2-dichloroethane (10 mL), to which sodium bis(acetyloxy)boranuidyl acetate (2.31 g, 10.91 mmol) was added. The mixture was stirred at room temperature for two days, then diluted with water (25 mL), extracted with dichloromethane (25 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to afford 849 mg of the product.
Reaction SMILES: C(OC([N:8]1[CH2:44][CH2:43][C:11]2([N:15]=[C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=4)=[C:30]([CH3:42])[CH:29]=3)[O:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:14]4[O:13][CH2:12][C:11]5([CH2:43][CH2:44][NH:8][CH2:9][CH2:10]5)[N:15]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][C:35]1[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6(CCN(C(=O)OC(C)(C)C)CC6)CO5)cc34)cc2C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6(CCNCC6)CO5)cc34)cc2C)cn1

Procedure:
N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diazaspiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS ESI (+) m/z 496 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 8.43 (s, 1H), 8.39 (s, 1H), 8.12 (d, 1H), 7.70 (m, 3H), 7.61 (dd, 1H), 7.28 (m, 2H), 6.98 (d, 1H), 3.45 (m, 2H), 3.32 (m, 2H), 3.25 (m, 2H) 2.50 (s, 3H), 2.32 (m, 2H), 2.25 (s, 3H), 2.01 (m, 2H).
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C.O>CC(O)C.C(Cl)Cl>[CH2:39]([O:38][C:36]([C:29]1[C:30]([C:32]([F:34])([F:35])[F:33])=[N:31][C:26]([N:9]2[CH2:8][CH2:7][N:6]3[C:10]4[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=4[N:12]=[C:5]3[C@H:4]2[CH:1]([CH3:3])[CH3:2])=[N:27][CH:28]=1)=[O:37])[CH3:40]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N2CCn3c(nc4cc(C(=O)OC)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (80 mg, 0.228 mmol) in iPrOH (2 mL) and DCM (1 mL) was added ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (174 mg, 0.684 mmol) and DIEA (177 mg, 1.37 mmol). The mixture was stirred at 60° C. overnight. Water (5 mL) was added to the mixture and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (2×10 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(5-(ethoxycarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (75 mg, 57.8% yield) as a yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]2[N:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:9]2[N:8]=1)(=O)=O.[C:32]([O:36][C:37]([NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCC>CN(C=O)C>[C:24]1([C:23]2[C:7]([C:47]3[CH:48]=[CH:49][C:44]([C:40]4([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:43][CH2:42][CH2:41]4)=[CH:45][CH:46]=3)=[N:8][N:9]3[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:12]([C:19]([F:20])([F:21])[F:22])=[N:11][C:10]=23)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B(O)O)cc2)CCC1
Reactant: O=S(=O)(Oc1nn2c(C(F)(F)F)cc(C(F)(F)F)nc2c1-c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(C(F)(F)F)cc(C(F)(F)F)nc4c3-c3ccccc3)cc2)CCC1
Temperature: 110 °C
Yield: 55 %

Procedure:
3-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl trifluoromethanesulfonate (230 mg, 0.46 mmol, 1 eq), (4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}-phenyl)boronic acid [Int-2A] (210 mg, 0.68 mmol, 85% purity, 1.5 eq), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (40.8 mg, 0.05 mmol, 0.11 eq) and cesium carbonate (371 mg, 1.14 mmol, 2.5 eq) were dissolved in 3.8 mL DMF and heated under microwave irradiation to a temperature of 110° C. After a hold time of 35 sec the reaction mixture was cooled to it and the volatile components were removed in vacuo. The resulting crude material was purified by preparative MPLC [Biotage Isolera: SNAP cartridge 25 g, hexane→hexane/ethyl acetate (2/1)] to yield a sample of insufficient purity. This was forwarded to another preparative MPLC with adapted gradient [Biotage Isolera: SNAP cartridge 25 g, hexane→hexane/ethyl acetate (4/1)] to give 160 mg (55%) of title compound in 90% purity (UPLC, area-%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[CH2:20][C:21]([CH3:23])=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:22][C:21]([CH3:23])=[CH2:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(NC2CCN(C(C)=O)CC2)c1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CN(c1cccc(OC)c1)C1CCN(C(C)=O)CC1
Yield: 63.6 %

Procedure:
A mixture of N-(l-acetylpiperidin-4-yl)-3-methoxyaniline (2.0 g), 3-chloro-2-methylpropene (10 ml) and potassium carbonate (5.0 g) in dimethylformamide (50 ml) was reacted at 80° C. for 6 hr. Then the reaction mixtures were concentrated under reduced pressure and partitioned between ethyl acetate and water. The ethyl acetate layer was washed successively with water and brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound (1.55 g) as a yellow oil (yield: 63.6%).