Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][NH:10][C:11](=[O:12])[CH:5]2[CH2:4][NH:3][CH2:2]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO.[OH-].[Na+]>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=4[CH2:9][NH:10][C:11](=[O:12])[CH:5]3[CH2:4]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1NCc2ccccc2N2CCNCC12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NCc2ccccc2N2CCN(Cc3ccc(F)cc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3,4,4a,6,7-Hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one (680.0 mg, 3.13 mmol, Example 2A) was dissolve in methanol (15 mL). 4-Fluorobenzaldehyde (653.5 mg, 5.27 mmol) was added to the reaction and stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (565.3 mg, 9.00 mmol) was then added, and the reaction was stirred at ambient temperature for 17 hours. The reaction was then diluted with 1 M NaOH (50 mL) and extract with dichloromethane (3×50 mL). The organic layers were combined, and purified by silica gel chromatography (ethyl acetate, Rf 0.40) to give the title compound: 1H NMR (400 MHz, benzene-d6) δ ppm 1.93 (td, J=11.0, 2.8 Hz, 1H), 2.42 (t, J=10.6 Hz, 1H), 2.49-2.51 (m, 1H), 2.60 (dt, J=11.0, 2.6 Hz, 1H), 2.85 (td, J=11.2, 2.9 Hz, 1H), 3.02-3.10 (m, 2H), 3.30 (d, J=13.2 Hz, 1H), 3.50 (dt, J=10.7, 2.3 Hz, 1H), 3.75 (dd, J=10.4, 2.8 Hz, 1H), 4.51 (dd, J=13.6, 4.0 Hz, 1H), 6.72-6.73 (d, J=8.1 Hz, 1H), 6.75 (dd, J=7.3, 1.5 Hz, 1H), 6.81-6.84 (m, 3H), 7.02-7.09 (m, 3H); MS (DCI/NH3) m/z 326 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18]C)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.B(Br)(Br)Br>C(Cl)Cl.C(OC)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(F)c2c1C1(CCCCC1)NC(=O)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=C1Nc2c(F)ccc(O)c2C2(CCCCC2)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a stirred solution of 8′-fluoro-5′-methoxy-1′H-spiro[cyclohexane-1,4′-quinazolin]-2′(3′H)-one (2.34 g, 8.84 mmol) in DCM (250 mL) at 0 to 5° C. was added boron tribromide (11.07 g, 44.2 mmol) dropwise over 20 minutes under N2. The mixture was stirred at 5° C. for 10 mins and gradually allowed to warm up to ambient temperature. Stirring was continued at ambient temperature for 18 h and a further portion of BBr3 (5 g, 20 mmol) was added. The mixture was left to stir for a further 24 hours and quenched with saturated NaHCO3 solution (500 mL) at 10° C. over 30 minutes. The mixture was stirred at ambient temperature for 1 hour and the aqueous layer was separated from dichloromethane and extracted with ethyl acetate (2×500 mL). The organic layers were washed with saturated NaHCO3 solution (200 mL), water (300 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo at 40° C. to give the crude product. The crude material was slurred in tert-butylmethylether (10 mL) at 18 to 20° C. for 5 minutes, filtered and dried in vacuo at 40° C. to give 8′-fluoro-5′-hydroxy-1′H-spiro[cyclohexane-1,4′-quinazolin]-2′(3′H)-one (1.5 g, 68%) as a light-brown solid, purity (99.9%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]3)[N:14]=2)[CH:5]=1)(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH3:65][N:66]([CH:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)[CH3:67]>C1COCC1>[CH3:65][N:66]([CH3:67])[CH:68]1[CH2:73][CH2:72][N:71]([C:26]([CH:23]2[CH2:24][CH2:25][CH:20]([NH:19][C:15]3[N:14]=[C:13]([N:6]4[C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]([C:1]([NH2:2])=[O:3])=[CH:5]4)[CH:18]=[CH:17][N:16]=3)[CH2:21][CH2:22]2)=[O:27])[CH2:70][CH2:69]1
Reactant: CN(C)C1CCNCC1
Reactant: NC(=O)c1cn(-c2ccnc(NC3CCC(C(=O)O)CC3)n2)c2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)C2CCC(Nc3nccc(-n4cc(C(N)=O)c5ccccc54)n3)CC2)CC1
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a suspension of 4-[4-(3-carbamoyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclo-hexanecarboxylic acid (150 mg, 0.395 mmol) in THF was added BOP, followed by Hünig's base (103 μL, 0.593 mmol), the mixture stirred for 10 min, and 4-(N,N-dimethylamino)-piperidine (76 mg, 0.593 mmol) was added and stirred for 6 days at RT. The resulting white solid was filtered off, washed with dry THF (20 mL) and DCM (30 mL), and air-dried overnight. The product was purified by prep-TLC using 5% MeOH/DCM+NH4OH, and dried under vacuum to provide 1-{2-[4-(4-dimethylamino-piperidine-1-carbonyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indole-3-carboxylic acid amide (78 mg, 40.3% yield) as a yellow solid (Compound 295).
Reaction SMILES: Cl.CO.C(=O)([S:6][CH:7]([CH2:9][C:10](=[O:15])[CH:11]([CH3:14])[CH2:12][CH3:13])[CH3:8])C>O>[SH:6][CH:7]([CH2:9][C:10](=[O:15])[CH:11]([CH3:14])[CH2:12][CH3:13])[CH3:8]
Reactant: CCC(C)C(=O)CC(C)SC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CCC(C)C(=O)CC(C)S
Temperature: 40 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
A reaction flask was charged with HCl (1.25 M, 500 mL) in methanol (0.63 mol). S-(5-methyl-4-oxoheptan-2-yl) ethanethioate (127.0 g, 0.63 mol) (synthesized as above in EXAMPLE I) then added into the reaction flask in one portion. The reaction mixture was stirred at 40° C. for about 48 hours, then cooled down to room temperature, and transferred into a separatory funnel Water (250 mL) was added. The reaction mixture was then extracted twice with ethyl acetate (250 mL each time). The organic phases were combined, washed with water (250 mL) followed by brine (100 mL), and then dried with magnesium sulfate. Further distillation of the obtained crude product under a vacuum (at 57° C. with a pressure of 1.33 mmHg) provided 2-mercapto-5-methyl-heptan-4-one (76.0 g) (about 76% yield with a purity over 98% monitored with gas chromatography).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C>Cl.O=[Pt]=O.C(Cl)(Cl)Cl>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(OCCN2CCOCC2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NCc1ccc(OCCN2CCOCC2)cc1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 4-[2-(4-morpholinyl)ethoxy]benzonitrile (0.93 g, 4 mmol), ethanol (100 ml), CHCl3 (4 ml) and PtO2 (100 mg) is hydrogenated at 45 psi on a Parr hydrogenator for 8 hours. Concentrated HCl (2-3 drops) is then added to the reaction mixture, and the hydrogenation is continued for another 10 hours. The catalyst is removed by filtration, the filter cake is washed with ethanol and then the filtrate is evaporated to dryness. The residue is dissolved in water and then is saturated with solid K2CO3. The mixture is extracted with CH2Cl2 and then the CH2Cl2 layer is dried over K2CO3 and evaporated to afford 0.75 g (79%) of 4-[2-(4-morpholinyl)ethoxy]phenylmethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:20])=[C:16]4[CH2:27][CH2:28][CH2:29][CH2:30][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[Li].O>CO.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:31]([F:32])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[C:16]4[CH2:27][CH2:28][CH2:29][CH2:30][C:15]=34)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 81.9 %

Procedure:
Stir a mixture of methyl 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetate (534 mg, 1.0 mmol) and LiOH—H2O (168 mg, 4.0 mmol) in MeOH (20 mL) and water (5 mL) at room temperature for overnight. After removal of organic solvent under vacuum, dilute the residue with ice water (10 mL). Acidify the aqueous mixture with conc. HCl to pH=1, and extract the resultant mixture with EtOAc (15 mL×3). The combined organic layers are washed brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 1:1) to afford 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetic acid as a pale yellow solid (427 mg, 82.0%). MS (m/z): 521 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:16]=2)[C:11](=[O:38])[C:10]([CH:39]=O)=[N:9]1)[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[C:15]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:16]=2)[C:11](=[O:38])[C:10]([CH2:39][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:9]1)[CH3:7]
Reactant: CCn1nc(C=O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1nc(CN2CCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reaction time: 1.5 h
Yield: 77.3 %

Procedure:
A solution of pyrrolidine (0.167 mL, 2.017 mmol) and 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde (0.87 g, 1.833 mmol) in 1,2-dichloroethane (DCE) (19 mL) and 2 drops of acetic acid was treated with sodium triacetoxyborohydride (0.583 g, 2.75 mmol). The reaction mixture was stirred for 1.5 h and then concentrated. The residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with [dichloromethane/methanol/ammonium hydroxide (80:20:2)]/dichloromethane (0-60%) to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)cinnolin-4(1H)-one (750 mg, 1.416 mmol, 77% yield) as a light yellow gummy solid. LCMS: (M+H)+: 530.3
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=1[CH:7]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=1[CH:7]=[CH:14][C:15](=[O:16])[CH3:17]
Reactant: CC(C)=O
Reactant: Cc1ccc(Cl)c(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(C)ccc1Cl
Reaction time: 1 h

Procedure:
To a mixture of acetone (160 ml), sodium hydroxide (2.6 g) and water (160 ml) was added dropwise at 0° C. a solution of crude 2-chloro-5-methylbenzaldehyde (18.3 g) in acetone (30 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(2-chloro-5-methylphenyl)-3-buten-2-one (18.9 g) as oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C[NH:12][CH2:13][C:14]1[N:15]=[C:16]([NH2:19])[S:17][CH:18]=1.C(N(CC)CC)C>C1COCC1>[NH2:19][C:16]1[S:17][CH:18]=[C:14]([CH2:13][NH:12][C:2]2[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=2)[N:15]=1
Reactant: CNCc1csc(N)n1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c(F)c(NCc2csc(N)n2)n1
Temperature: 25 °C
Yield: 62 %

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (480 mg, 2.65 mmol) was dissolved in 20 mL of THF and stirred at room temperature. (4-[(Methylamino)methyl]-1,3-thiazol-2-amine (2.65 mmol, theoretical) was added, followed by triethylamine (400 μL, 2.92 mmol). The resulting reaction mixture was stirred overnight and evaporated. The residue was stirred in water and the solid precipitate was collected by filtration and was dried in vacuo to provide N-[(2-amino-1,3-thiazol-4-yl)methyl]-6-chloro-5-fluoro-2-methyl-4-pyrimidinamine (450 mg, 59%) that was used without further purification. LCMS: (M+H)+: 288.1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH:17]1([CH2:22][C:23](O)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:16])[N:2]([NH:1][C:23](=[O:24])[CH2:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: O=C(O)CC1CCCC1
Reactant: CC(C)(C)c1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)c1nn(NC(=O)CC2CCCC2)c(=O)c2ccccc12

Procedure:
The product from Example 62A and 2-cyclopentylacetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.18 (s, 1H), 8.39 (d, J=2.0 Hz, 2H), 7.93-8.00 (m, 1H), 7.87 (t, J=7.5 Hz, 1H), 2.20-2.31 (m, 3H), 1.74-1.90 (m, 2H), 1.47-1.70 (m, 4H), 1.47 (s, 9H), 1.17-1.33 (m, 2H); MS (ESI+) M/Z 328 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1
Reactant: Clc1cccc(CBr)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(OCC3CCN(Cc4cccc(Cl)c4)CC3)cccc2n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (2.5 g, 9.15 mmol) and diisopropylethylamine (2.96 g, 22.87 mmol) in DMF (16 mL) was added a solution of 3-chlorobenzyl bromide in DMF (4 mL). The reaction mixture was heated at 60° C. with stirring for 20 h. The mixture was concentrated, water was added stirred for 1 h. The precipitate was filtered, washed with water, dried. Purified by silica gel column chromatography using 3-10% methanol in dichloromethane afforded 1.82 g of 5-[1-(3-chlorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.38 (m, 5H), 7.2 (s, 2H), 6.77 (dd, J=8.0, 1.2 Hz, 1H), 6.53 (dd, J=8.0, 0.8 Hz, 1H), 5.95 (s, 2H), 3.99 (d, J=6.4 Hz, 2H), 3.48 (s, 2H), 2.84 (d, J=11.2 Hz, 2H), 1.7-2.07 (m, 5H), 1.3-1.42 9m, 2H). MS m/z (ESI) 399 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[Si](I)(C)(C)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under exclusion of moisture, to 500 mg (1.76 mmol) of 1-chloro-4-[(6-methoxy-pyridin-3-yl)methyl]-isoquinoline (step 28.6) in 9 ml of chloroform, 488 μl (3.58 mmol) of Me3SiI are added. Then the mixture is stirred for 8 h at 60° C. Dilution of the mixture with EtOAc and NaHCO3-solution, stirring and filtration of the suspension yields 1-chloro-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline, contaminated with 1-iodo-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline; FAB-MS: (M+H)+=271chloride/363iodide; HPLC(gradient20-100) tRef=10.2chloride/10.8iodide. From the filtrate, more product can be obtained by extraction with EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[CH2:12]Br.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][O:14][CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CCOCC1
Yield: 58.9 %

Procedure:
(1S)-(−)-1-(4-Bromophenyl)ethylamine (2.4 g), 2,2′-dibromodiethylether (3.25 g) and N,N-diisopropylethylamine (6 ml) were heated to 100° C. in dimethylformamide (40 ml) for 18 h, allowed to cool and partitioned between water and ethyl acetate. The organic phase was dried (MgSO4), evaporated under vacuum and purified by column chromatography using a 0-40% ethyl acetate/iso-hexane gradient. The product was obtained as a yellow oil (1.91 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([I:13])[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26]Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:24][O:25][CH3:26])=[C:6]([I:13])[CH:5]=1
Reactant: COC(=O)c1cc(I)c(O)c(OC)c1
Reactant: COCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(I)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 4-hydroxy-3-iodo-5-methoxybenzoic acid methyl ester (4.6 g) in chloroform (30 mL) were successively added diisopropylethylamine (3.88 g) and chloromethyl methyl ether (1.88 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with ethyl acetate, 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with solvent (hexane:ethyl acetate=3:1, v/v) to give the title compound (2.70 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si]([O:32][CH2:33][CH2:34][C:35]1[C:36]([F:53])=[C:37]([CH:50]=[CH:51][CH:52]=1)[CH2:38][N:39]1[CH2:49][CH2:48][C:42]2([O:47][CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40]1)(C(C)(C)C)(C)C.[CH2:54]([C:56]1[S:60][CH:59]=[C:58]([C:61](O)=[O:62])[CH:57]=1)[CH3:55].C(N(CC)CC)C>CN(C=O)C>[CH2:54]([C:56]1[S:60][CH:59]=[C:58]([C:61]([N:44]2[CH2:43][C:42]3([CH2:41][CH2:40][N:39]([CH2:38][C:37]4[CH:50]=[CH:51][CH:52]=[C:35]([CH2:34][CH2:33][OH:32])[C:36]=4[F:53])[CH2:49][CH2:48]3)[O:47][CH2:46][CH2:45]2)=[O:62])[CH:57]=1)[CH3:55]
Reactant: CCc1cc(C(=O)O)cs1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.316 g) was added in one portion to a solution at 0° C. of 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.271 g) and 5-ethylthiophene-3-carboxylic acid (0.1 g) and triethylamine (0.36 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF (20 mL) and treated with tetrabutylammonium fluoride (1M in THF, 1.921 mL). The reaction mixture was allowed to stand at 20° C. for 18 hours and the solvent was then removed under reduced pressure. The crude product was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.12 g.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]([C:8](=[O:25])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=2[F:24])[CH:10]=1)[CH3:7])C.[F:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:7][N:6]([CH2:5][C:4]([OH:3])=[O:26])[C:8](=[O:25])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=3[F:27])=[CH:19][C:18]=2[F:24])[CH:10]=1
Reactant: OB(O)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)CN(C)C(=O)c1cccc(COc2ccc(Br)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(=O)O)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2F)c1
Temperature: 150 °C

Procedure:
A mixture of {{[3-(4-bromo-2-fluoro-phenoxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester (600 mg, 1.51 mmol), 2,4,5-trifluorophenylboronic acid (400 mg, 2.27 mmol), Pd(dppf)Cl2 methylene chloride complex (37 mg, 0.045 mmol), potassium carbonate (520 mg, 3.8 mmol), DMF (12 mL) and water (3 mL) was degassed, flashed with nitrogen, heated at 150° C. for 60 minutes in microwave reactor. The mixture was acidified by conc. HCl and diluted with water. Solvent was then removed by decantation and the sticky residue was purified by preparative HPLC to afford {{methyl-[3-(3,2′,4′,5′-tetrafluoro-biphenyl-4-yloxymethyl)-benzoyl]-amino}-acetic acid, 171 mg (25%). LC-MS (ES) calculated for C23H17F4NO4, 447; found m/z 448 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH:67]1(O)[CH2:70][CH2:69][CH2:68]1>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH:67]2[CH2:70][CH2:69][CH2:68]2)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: OC1CCC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(C(C)=O)C2CCC2)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (50 mg) was reacted with cyclobutanol according to General Procedure W to give (S)-2-({(S)-7-[2-(acetyl-cyclobutyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]-isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This product (16 mg) was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 964.