Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(CO)CCCCC=1.[Cl:9][C:10]1[C:11]([O:21][CH:22]2[CH2:27][CH2:26][C:25](=[CH2:28])[CH2:24][CH2:23]2)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]>>[Cl:9][C:10]1[C:11]([O:21][CH:22]2[CH2:27][CH2:26][C:25]3([CH2:1][CH2:28]3)[CH2:24][CH2:23]2)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: OCC1=CCCCC1
Reactant: C=C1CCC(Oc2cc(F)c(C(=O)OC)cc2Cl)CC1
Product: COC(=O)c1cc(Cl)c(OC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 342 Step 2 and making non-critical variations to replace cyclohexenylmethanol with methyl 5-chloro-2-fluoro-4-((4-methylenecyclohexyl)oxy)benzoate, the title compound was obtained as a colorless syrup (0.769 g, 85% yield): 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J=7.7 Hz, 1H), 6.68 (d, J=12.4 Hz, 1H), 4.49-4.41 (m, 1H), 3.88 (s, 3H), 1.99-1.78 (m, 4H), 1.53-1.32 (m, 4H), 0.33-0.27 (m, 4H).
Reaction SMILES: [F:1][C:2]1(C(OCC)=O)[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.CS(C)=O.O.[Li+].[Cl-]>CCOC(C)=O>[F:1][CH:2]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)CC1
Temperature: 125 °C
Reaction time: 5 h
Yield: 55.8 %

Procedure:
To a 500 mL flask containing the product from Step A (23.5 g, 77.5 mmol) was added DMSO (160 mL) followed by H2O (6.98 mL, 387 mmol) and then LiCl (16.4 g, 387 mmol). The mixture was warmed to 125° C. and stirred for 5 hours. The resulting dark mixture was then cooled to ambient temperature and diluted with EtOAc (500 mL) and washed with a saturated aqueous NaHCO3:water (1:1, 3×250 mL). The combined aqueous phase was washed with EtOAc (100 mL) and the combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude oil was purified by column chromatography (10 to 30% EtOAc/hexanes) to provide 10.0 g (56%) of the desired product as a light golden oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].S(=O)(=O)(O)O.O.[CH3:19]O>CCOC(C)=O>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:19])=[O:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CO
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Yield: 69 %

Procedure:
A solution (0.5 M) of 5-methyl-4-nitrothiophene-2-carboxylic acid in methanol was treated with sulfuric acid (3.5 eq.). The reaction mixture was heated to reflux for 48 h. After cooling down, solvent was evaporated giving a residue that was dissolved in AcOEt and water was added. The organic phase was separated and the aqueous layer was extracted with AcOEt. The combined organic phase was washed sequentially with aqueous NaHCO3 (saturated solution) and brine, then dried and concentrated giving the title compound (69%) as solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4][CH2:3]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[C:21]1([NH:27][C:28]([NH:1][CH:2]2[CH2:20][C:6]3[C:7]4[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=4[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=3[CH2:4][CH2:3]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
The product of Example 15 (0.15 g, 0.5 mmol), phenylisocyanate (0.1 g, 1 mmol) and triethylamine (0.1 g) in 5 mL dimethylformamide were stirred at room temperature for 18 h. The solvent was removed by rotoevaporation and the residue suspended in methanol/dimethylformamide. After heating, the solid was collected by filtration and dried in vacuo. CHN calc'd for C19H17N5O5.0.5H2O.HCON(Me)2 : C, 55.34; H, 5.27: N, 17.60 found-C, 55.38: H, 4.95; N, 17.04. H-NMR (400 MHz, dmso) 1H, s, 12.1; 1H, s, 11.45; 1H, s, 8.4; 1H, s, 7.95; 1H, s, 7.7; 2H, d, 7.4; 2H, t, 7.23; 1H, t, 6.9 1H, d, 6.35; 1H, t, 4.1; +ring protons.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C=O)C>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:18][C:5]1[C:4]([Br:3])=[CH:13][C:12]2[C:11]([CH3:14])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:16])[C:7]=2[CH:6]=1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
720 mg (24 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. A solution of 5.7 g (20 mmol) of 3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol dissolved in 75 ml of DMF are added dropwise and the mixture is stirred until the evolution of gas has ceased. 6.8 ml (59.3 mmol) of methoxyethoxymethyl chloride are then added at 0° C. and the mixture is stirred for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 16.6 g (91%) of the expected product are collected in the form of an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]([C:49]([O:51]C)=[O:50])[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1.Cl.Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@@H:42]([C:49]([OH:51])=[O:50])[CH2:43][C:44]3[N:48]=[CH:47][NH:46][CH:45]=3)=[O:37])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](N)Cc1c[nH]cn1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@H](Cc3c[nH]cn3)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-D-His-OMe.2HCl (48 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ13.88-14.43 (m, 1 H), 8.96 (d, 2 H), 8.20 (d, 1 H), 7.38 (s, 1 H), 7.26 (m, 5 H), 7.20 (m, 1 H), 7.13 (d, 4 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.43-4.70 (m, 1 H), 4.04 (d, 4 H), 3.14 (m, 1 H), 2.98 (m, 1 H), 2.92 (s, 3 H), 2.39 (s, 3 H), 2.36 (m, 2 H), 2.09 (m, 2 H), 1.71 (m, 2 H); MS (APCI+) m/z 696 (M+H)+.
Reaction SMILES: C([NH:8][C@H:9]([CH:14]=O)[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[NH2:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:14][N:34]1[CH2:33][CH2:32][CH:31]([N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:29][CH:28]=2)[CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH2:36][CH2:35]1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C[C@@H](N)CC(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
Boc-L-leucinal (0.78 g, 3.64 mmol) was treated with a solution of (4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (1.28 g, 3.64 mmol) in CH2Cl2 (36 mL), stirred 15 minutes, cooled to 0° C., and treated with NaBH(OAc)3 (1.16 g, 5.46 mmol). The reaction was allowed to warm to RT as ice melted and stir 4 hours. The reaction was diluted with EtOAc (200 mL), washed with saturated bicarbonate solution, and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 8% MeOH/CH2Cl2 to give 1.15 g (57%) of the desired product (Id).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[NH:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[C:26]([O:25][C:23]([NH:14][C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:20]([O:22][CH2:2][C:3]#[N:4])=[O:21])=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reaction time: 12 h
Yield: 96 %

Procedure:
Chloroacetonitrile (5 mL) and DIPEA (160 mg, 0.21 mL, 1.2 mmol) were added to Boc-Leu-OH (252 mg, 1.09 mmol) and stirred for 12 h. The solvent was removed under reduced pressure and SiO2 flash chromatography (20% ethyl acetate in hexanes) afforded 284 mg of a pale yellow oil in 96% yield. Rf 0.5 in 20% ethyl acetate in hexanes. 1H NMR (500 MHz, CDCl3): δ 5.00 (d, J=7.7 Hz, 1H), 4.80-4.65 (m, 2H), 4.30-4.29 (m, 1H), 1.70-1.65 (m, 1H), 1.60-1.47 (m, 2H), 1.39 (s, 9H), 0.91-0.89 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 172.2, 155.5, 114.21, 80.3, 53.2, 52.0, 41.0, 28.3, 24.8, 22.8, 21.7; HRMS (ESI) m/z calcd for C13H22N2O4Na [M+Na]+ 293.147. found 293.151.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[N:15]([CH3:16])[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=1)(=[O:10])=[O:9].[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)(=[O:10])=[O:9])[CH:25]=[CH:24][C:23]=1[C:37]1[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=1
Reactant: Cn1c(S(=O)(=O)c2ccccc2Br)nc2ccccc21
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Cn1c(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)nc2ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-((2-bromophenyl)sulfonyl)-1-methyl-1H-benzo[d]imidazole and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C24H18FN5O2S, 459.12; m/z found, 460.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.03-6.96 (dd, J=7.8, 1.5, 1H), 6.88-6.86 (d, J=1.4, 2H), 6.43-6.28 (m, 1.5, 2H), 6.15-6.09 (d, J=8.2, 1H), 6.08-5.99 (m, 2H), 5.97-5.86 (m, 2H), 5.64-5.53 (m, 1H), 5.34-5.30 (dd, J=7.8, 1.7, 1H), 5.30-5.23 (dd, J=11.3, 1.7, 1H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH:5]1[CH3:25])#[N:2].[F:26][C:27]([F:32])([F:31])[C:28](O)=[O:29]>>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:28](=[O:29])[C:27]([F:32])([F:31])[F:26])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH:5]1[CH3:25])#[N:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1CN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CCC1=CC#N
Product: CC1CN(c2ccc(N3C[C@H](CNC(=O)C(F)(F)F)OC3=O)cc2F)CCC1=CC#N
Yield: 51 %

Procedure:
The title compound was prepared as per Example-29 by using (S)-N-{3-[4-(4-cyanomethylidene-3-methylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and trifluoroacetic acid in 51% yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][N:31]([CH3:45])[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:35]2([OH:38])[CH2:36][CH2:37][C:32]([N:31]([CH3:30])[CH3:45])([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:33][CH2:34]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
A solution of 1-benzenesulfonyl-1H-indol (600 mg, 2.33 mmol) in dry THF (30 ml) was cooled to −5° C. under a stream of argon. n-butyllithium (2.79 mmol, 1.75 ml of a 1.6 molar hexane solution) were added dropwise in such a way that a reaction temperature of 0° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2 hours at 0° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (493 mg, 2.33 mmol) in dry THF (5 ml) was added dropwise at 0° C. The mixture was stirred for 1 hour at 0° C. and then 3 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out by flash chromatography with cyclohexane/ethylacetate (V:V=1:1) over silica gel. 232 mg 1-(1-benzenesulfonyl-1H-indol-2-yl)-4-dimethylamino-4-phenylcyclohexanol with a melting point of 173–176° C. were obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4([NH:47]C=O)[CH2:25][CH2:24][N:23]([CH2:26][C:27](=[O:46])[N:28]5[CH2:33][CH2:32][N:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:45]=[CH:44][CH:43]=[CH:42][N:41]=7)=[CH:36][CH:35]=6)[CH2:30][CH2:29]5)[CH2:22]4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4([NH2:47])[CH2:25][CH2:24][N:23]([CH2:26][C:27](=[O:46])[N:28]5[CH2:29][CH2:30][N:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:41]=[CH:42][CH:43]=[CH:44][N:45]=7)=[CH:36][CH:35]=6)[CH2:32][CH2:33]5)[CH2:22]4)=[O:20])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=CNC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75.3 %

Procedure:
Added 2M HCl (2 ml) to a solution of 3-Formylamino-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (6P) (10 mg, 0.015 mmol) in MeOH (2 ml) at room temperature, then stirred for 4 days at room temperature. The reaction mixture was diluted with Water (20 ml), basified with 1N NaOH (3 ml) and extracted with MeCl2 (3×50 ml). The organic layers were combined, dried over MgSO4, filtered and solvent evaporated yielding 7P as a white solid (7 mg, 73%) LCMS (MH 620.3) Retention time=2.78 minutes.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24](Cl)=[C:23](Cl)[N:22]=[C:21](Cl)[C:20]=2Cl)[CH:13]([OH:29])[CH2:12]1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Pd]>[N:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH:13]2[OH:29])=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)C(O)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC1CNCCC1CNc1ccncc1

Procedure:
A suspension of 3-hydroxy-4-[(2,3,5,6-tetrachloro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester compound from Step 1 above (1.64 g) and potassium carbonate (6 g) in ethanol (200 mL) was hydrogenated at 60 psi over 1 g of 10% palladium on charcoal for 5 h. The reaction mixture was filtered and the solids washed well with ethanol. The filtrate was evaporated, taken up in 40% MeOH DCM and refiltered. The filtrate was evaporated to give crude 4-(pyridin-4-ylaminomethyl)-piperidin-3-ol product used without further purification in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:11])=[C:5]([NH:9]N)[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.C(O)(=O)C>C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:9][C:5]3[C:6]([CH:22]=2)=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=3[F:11])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cc3ccc(Cl)c(F)c3[nH]2)cc1
Temperature: 105 °C

Procedure:
(3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride (Apollo Scientific, Ltd., 221 mg, 1.12 mmol) and 4-acetyl-benzoic acid methyl ester (200 mg, 1.12 mmol) are treated with anhydrous ZnCl2 (382 mg, 2.81 mmol) and acetic acid (10 mL). The reaction is heated to 105° C. for 48 hours. After cooling to room temperature, the reaction is diluted with ethyl acetate and sequentially washed with H2O (5×) followed by saturated aqueous NaCl. The organics are then dried over Na2SO4 and filtered. After concentration, the crude product is purified by preparative RP LC-MS to give 4-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester as an off-white solid: ESMS m/z 304.0 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([O:11][CH:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1)(=O)=O.[CH2:22]([N:29]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][C:34]([O:41][CH3:42])=[C:35](O)[CH:36]=2)[N:31]=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([N:29]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][C:34]([O:41][CH3:42])=[C:35]([O:11][CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[CH:36]=2)[N:31]=[CH:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
16.0 g potassium carbonate and 20.0 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are added at 50° C. to 20.0 g 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline in 150 ml N,N-dimethylformamide and the mixture is vigorously stirred for 18 hours at 80° C. To complete the reaction potassium carbonate and 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are each added three times and in each case the mixture is stirred for several hours at 80° C. The reaction mixture is cooled and slowly combined with a total of 500 ml of water. The precipitate is suction filtered, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][N:5]2S(C1C=CC(C)=CC=1)(=O)=O.ClCCl.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:15])([F:14])[F:16])[C@@H:7]([CH3:18])[CH2:6][NH:5]2
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)N(C(=O)C(F)(F)F)c3ccc(Br)cc32)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A 3-L, three-necked, round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and thermocouple was charged with (S)-1-(6-bromo-2-methyl-4-tosyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (106.81 g, 224 mmol), dichloromethane (1070 mL), and sulfuric acid (18 M, 119 mL, 2238 mmol). The reaction mixture stirred at rt for 1 h and was then cooled to 0° C. Water (1070 mL) was slowly added in 100 mL portions, while maintaining the internal temperature at ca. 0° C. (Note: the internal temperature rose from ca. 2.6° C. to 23.8° C. with each addition). After the final water addition, the internal temperature was 34° C., and the mixture was cooled to rt. The aqueous layer was separated extracted with dichloromethane (700 mL). The combined organic layers were washed with water (700 mL) and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 100% dichloromethane). The product-containing fractions were combined and concentrated under reduced pressure. Further drying under vacuum (ca. 17 Torr) at rt afforded (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (71.8 g, 99%) as a brown solid. MS (ESI, pos. ion) m/z 323[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[K+].O1CCO[CH2:18][CH2:17]1>>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]3[C:2]=2[N:1]=[CH:18][CH:17]=[CH:12]3)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1c(C=O)ccc2cccnc12
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Product: c1cnc2c(c1)ccc1cccnc12

Procedure:
2.5 g of 2,2′-dibromobiphenyl, 3.9 g of 3-acetylphenyl-boronic acid, 21 ml of 2M sodium carbonate and 0.37 g of tetrakis(triphenylphosphine)palladium(0) were added to 200 ml of 1,2-dimethoxyethane, and refluxing carried out for 10 hours under nitrogen so that a Suzuki coupling reaction was performed and, by treatment in the normal way, 0.57 g of 2,2′-bis(3-acetylphenyl)biphenyl was obtained. 0.57 g of this diacetyl derivative was reacted with 0.63 g of 8-amino-7-quinolinecarbaldehyde and 0.6 g of potassium hydroxide in dioxane at 60° C. and, by treatment in the normal way, Phen-3 (0.76 g) shown below was obtained. 1H-NMR (CDCl3, ppm) 9.20 (d·d, 2H), 8.43 (d, 2H), 8.16 (d·d, 2H), 7.79 (d, 2H), 7.61−7.26 (m, 18H), 7.17 (t, 2H), 6.77 (d, 2H)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[O-].[Na+].CO.C(O)(=[S:18])C>CO>[SH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)=S
Reactant: Clc1ccc2nccn2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Sc1ccc2nccn2n1
Temperature: 150 °C
Yield: 27.8 %

Procedure:
6-Chloroimidazo[1,2-b]pyridazine (13.5 g), 28 W/W % sodium methoxide-methanol solution (17.5 g) and thioacetic acid (7.0 g) were dissolved in 70 ml of methanol and this solution was heated at 150° C. in a sealed tube for 6 hours. The reaction mixture was cooled to room temperature and distilled to remove the organic solvent. The residue was washed three times with chloroform, and the insoluble material was extracted six times with 50 ml of chloroform-methanol (1:1) solution. The combined extracts were distilled to remove the organic solvent. The precipitated crystals were collected by filtration, thereby obtaining 3.7 g of 6-mercaptoimidazo[1,2-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[CH2:8][C@H:7]([NH2:21])[C:6]1=[O:22].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[CH2:8][C@H:7]([N:21]=[CH:34][C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[C:6]1=[O:22]
Reactant: COCC(=O)N1C[C@H](N)C(=O)N(CC(=O)OC)c2ccccc21
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COCC(=O)N1C[C@H](N=Cc2ccc3ccccc3c2)C(=O)N(CC(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
To a solution of 638 (630 mg, 1.76 mmol) and 2-naphthylmethyl bromide (428 mg, 1.94 mmol) in CH3CN was added K2CO3 (608 mg, 4.4 mmol). The resulting mixture was stirred at ambient temperature. After 18 hours, the reaction mixture was diluted with CH2Cl2, washed with water then brine, dried over Na2SO4 then concentrated in vacuo. Flash chromatography (SiO2, 0 to 20% EtOAc/CH2Cl2) afforded 450 mg of 639.