Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[N:3]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)Oc1nc(Cl)ccc1C(N)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)Oc1nc(Cl)ccc1C#N
Temperature: 55 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 6-chloro-2-isopropoxy-nicotinamide (2.87 g, 13.37 mmol) and pyridine (6.48 mL, 80.22 mmol) in acetonitrile (25 mL) was added phosphorus oxychloride (3.68 mL, 40.13 mmol) over a period of 5 min. The reaction was stirred at 55° C. for 1 h. Acetonitrile was evaporated in vacuo and the resulting residue was neutralized with 1N NaOH at 0° C. until pH reached to ˜7. The reaction mixture was extracted with EtOAc (100 mL). The organic layer was collected and the aqueous layer was further extracted with EtOAc (3×50 mL). All organics were combined washed with brine (2×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (2.1 g, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 5.34-5.20 (m, 1H), 1.33 (d, J=6.2 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[Br:27][CH2:28][C:29](Br)=[O:30]>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[C:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]([C:29](=[O:30])[CH2:28][Br:27])[CH2:4][CH2:3]1
Reactant: CN1CCNc2c(C(=O)c3ccccc3F)cccc21
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(C(=O)CBr)c2c(C(=O)c3ccccc3F)cccc21

Procedure:
To a solution of 1-methyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline (11.99 g) and pyridine (4.04 g) in methylene chloride (200 ml) was dropwise added a solution of bromoacetyl bromide (5.09 ml) in methylene chloride (10 ml) under stirring at a temperature below 10° C. and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was washed with water twice and dried. Removal of the solvent afforded viscous oil. The viscous oil was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried to give 1-methyl-4-bromoacetyl-5-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline (17.18 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:32])[C:27](=[O:31])[CH2:28][O:29][CH3:30])=[N:24][CH:25]=1>>[CH3:30][O:29][CH2:28][C:27]([N:26]([CH3:32])[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1)=[O:31]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COCC(=O)N(C)c1ccc(N)cn1
Product: COCC(=O)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-acetyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(5-amino-pyridin-2-yl)-2-methoxy-N-methyl-acetamide. LCMS calcd for C20H17F3N4O4 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][CH2:13][O-:14].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:14][CH2:13][CH3:12])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (3 g, 13.6 mmol) and EtOH (50 mL) was added NaOEt (21% w/w, 50 mL). The mixture stirred for 2 h before concentrating in vacuo. The residue purified by flash chromatography (0-100% EtoAc/Hexane) to afford 62A (3 g, 90%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (t, 3 H) 4.19 (q, 2 H) 7.22 (dd, 2 H) 7.71-7.81 (m, 1 H).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH2:7][C:6](=O)[C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2:12][OH:13].C(O)C>N1C=CC=CC=1>[OH:13][N:12]=[C:6]1[CH2:7][CH:8]=[CH:9][C:10]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1CC=Cc2cnccc21
Reactant: NO
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CC=Cc2cnccc21
Yield: 61.8 %

Procedure:
Isoquinolin-5-one (21.57g, 0.147M) and hydroxylamine (15.55g, 0.22M) together with approximately 300 ml of dry ethanol and 75 ml of pyridine were stirred at reflux temperature of the mixture for 6 hours. The solvent was then removed by evaporation and the residue was dissolved in a mixture of diethyl ether and water (600 ml, ca. 1:1). The organic phase was separated and extracted with water to remove residual pyridine, washed with saturated, aqueous solution of sodium chloride and dried over magnesium sulfate crystals. The inorganic matter was removed by filtration and the solvent by evaporation leaving 14.7 grams of the desired product (61.7% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-])=O.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[NH2:1][C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([N:27]1[CH2:28][CH2:29][N:24]([C:18]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=2[CH3:16])[CH2:25][CH2:26]1)=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N)CC2)c(C)c1
Yield: 95 %

Procedure:
Using 2,4-dinitrobenzoic acid (585 mg) and 1-(2,4-dimethylphenyl)piperazine (523 mg) and by the reaction and treatment in the same manner as in Preparation Example 148, the title compound (847 mg) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.FC(F)(F)S(O[C:16]1[C:17]2[CH2:37][N:36]([C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][C:18]=2[N:19]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[CH:25][CH:24]=2)[N:21]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:16]1[C:17]2[CH2:37][N:36]([C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][C:18]=2[N:19]=[C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[CH:27][CH:28]=2)[N:21]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CNCc1ccccn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)Cc3ccccn3)c2C1
Yield: 12 %

Procedure:
1-(4-(Methyl(pyridin-2-ylmethyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (8.8 mg 12%) was prepared from N-methyl-1-(pyridin-2-yl)methanamine and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([F:12])[CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:35]1[CH2:38][CH:37]([C:39]2[C:40]([C:45]3[CH:54]=[CH:53][C:48]([C:49]([NH:51][CH3:52])=[O:50])=[C:47]([F:55])[CH:46]=3)=[N:41][CH:42]=[CH:43][N:44]=2)[CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[N:11][C:2]([N:35]3[CH2:36][CH:37]([C:39]4[C:40]([C:45]5[CH:54]=[CH:53][C:48]([C:49]([NH:51][CH3:52])=[O:50])=[C:47]([F:55])[CH:46]=5)=[N:41][CH:42]=[CH:43][N:44]=4)[CH2:38]3)=[N:3]2)=[CH:8][C:7]=1[F:12]
Reactant: Fc1cc2cnc(Cl)nc2cc1Cl
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CNC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(c3ncc4cc(F)c(Cl)cc4n3)C2)cc1F
Temperature: 100 °C
Yield: 70.4 %

Procedure:
A mixture of 2,7-dichloro-6-fluoroquinazoline (46 mg, 0.21 mmol), 4-(3-(azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate) (0.15 g, 0.23 mmol), and potassium carbonate (0.15 g, 1.06 mmol) in DMSO (1 mL) was heated to 100° C. for 1 h, then cooled to RT. Water was added, then the product was extracted into EtOAc. The combined extracts were washed with water (2×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel chromtography to give 4-(3-(1-(7-Chloro-6-fluoroquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide as a light yellow solid (69 mg, 70% yield). m/z=467 (M+1). 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.09 (d, J=4.70 Hz, 3 H) 4.28-4.38 (m, 1 H) 4.45-4.54 (m, 4 H) 6.80 (br. s., 1 H) 7.32-7.42 (m, 3 H) 7.71 (d, J=6.65 Hz, 1 H) 8.27 (t, J=7.92 Hz, 1 H) 8.58 (d, J=1.76 Hz, 1 H) 8.65 (s, 1 H) 8.94 (s, 1 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][N:9]2[S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: ClCCOc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ncc2c(OCCCl)cccc21
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-(2-chloroethoxy)-1H-indazole (1.1 g, 5.59 mmol) in tetrahydrofuran is treated with NaH (0.335 g, 60% in mineral oil, 8.39 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with benzenesulfonyl chloride (0.86 ml, 6.71 mmol), stirred at room temperature for 18 hr, quenched with water and diluted with ethyl acetate. The phases are separated and the organic phase is washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to give the desired product as a white solid, 1.75 g (93%), mp 102-104° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[N:11]2[N:12]=[C:13]([CH2:15][CH3:16])[CH:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[Br:5][C:6]1[N:11]2[N:12]=[C:13]([CH2:15][CH3:16])[C:14]([N+:1]([O-:4])=[O:2])=[C:10]2[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1cc2cccc(Br)n2n1
Agent: O=S(=O)(O)O
Product: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Fuming nitric acid (1.7 mL) was added dropwise to a solution of 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (6.9 g, 34.2 mmol) in concentrated sulfuric acid (13.8 mL) at an internal temperature of below 30° C. while cooling with ice. After stirring the reaction mixture for 30 minutes, it was added to ice water (138 mL) and the precipitate was filtered out. The obtained precipitate was added ethyl acetate (226 mL) and methanol (38 mL), and the mixture was heated to 70° C., and then the precipitate was collected by filtration while cooling with ice. The solvent of the obtained filtrate was evaporated under reduced pressure, and the concentrated residue was recrystallized from heptane-ethyl acetate (1:1) to afford 2.4 g of the title compound as light brown crystals (31% yield).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([O:12][CH:13]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[CH2:30][CH3:31]>>[C:33]1([C:29]([CH2:30][CH3:31])=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:28][CH:27]=2)[C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]3[CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:25][CH:26]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)c3ccc(O)cc3)cc2)C1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OC2CCNC2)cc1)c1ccccc1
Yield: 85.6 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, tert-butyl 3-(4-(4-hydroxybenzoyl)phenoxy)pyrrolidine-1-carboxylate (395 mg, 1.03 mmol) was reacted with propiophenone (276 mg, 2.06 mmol) to give 340 mg desired product (86% yield, Z/E=1/1) as a light yellow solid. m/z=386[M+1]+.
Reaction SMILES: [C:1]1(=[C:11]2C3C(=CC=CC=3)C(=N)[NH:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=N)[NH:2]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[CH2:23][C:22]1=[O:32]>CN1C(=O)CCC1.C(O)(=O)C>[O:32]=[C:22]1[C:23](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[C:11]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3](=[C:23]4[C:24](=[O:31])[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][C:22]4=[O:32])[NH:12]3)[NH:2]2)[C:24](=[O:31])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:21]1
Reactant: N=C1NC(=C2NC(=N)c3ccccc32)c2ccccc21
Reactant: O=C1CC(=O)c2ccccc2N1
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C(=O)C1=c1[nH]c(=c2[nH]c(=C3C(=O)Nc4ccccc4C3=O)c3ccccc23)c2ccccc12
Temperature: 25 °C

Procedure:
5.0 g of [1,1′]biisoindolylidene-3,3′-diimine and 14.9 g of 1H-quinoline-2,4-dione are stirred in a mixture of 90 ml of NMP and 10 ml of glacial acetic acid at reflux for 6 hours. After cooling to room temperature the suspension is filtered and the filter product is washed with ethanol and then water and dried at 60° C. This gives 6.2 g (59%) of a virtually black powder of a compound of the following formula
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[OH:25])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(O)c1ccccc1O
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3ccccc3O)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 2-hydroxybenzoic acid as brown solid (56%). MS 452 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: CCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (130 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (278 mg, 0.43 mmol, 82% yield) as a yellow oil: LCMS (ES) m/e 581 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:31]1([CH2:39]I)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:39][CH:31]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ICC1CCCCCCC1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CC1CCCCCCC1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a stirred solution of (Benzhydrylidene-amino)-acetic acid tert-butyl ester (3.00 g; 10.1 mmol) in 60 mL of tetrahydrofuran under argon at −78° C. was added lithium diisopropylamide solution (11.5 mL; 1.5 M solution in cyclohexane) dropwise. After 30 minutes, a solution of cycloheptylmethyl iodide (Prepared in Step A; 3.83 g; 15.2 mmol) was added dropwise via syringe and the mixture allowed to warm to room temperature and stirred for 18 h. The mixture was quenched with saturated sodium bicarbonate solution and most of the tetrahydrofuran was removed in vacuo. The mixture was diluted with water and extracted with methylene chloride. The combined extracts were dried (sodium sulfate) filtered and concentrated in vacuo. The crude product was chromatographed (eluent:4% ethyl acetate/hexanes) to give 3.34 g (79%) of 2-(Benzhydrylidene-amino)-3-cyclooctyl-propionic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1O.P(Cl)(Cl)[Cl:13].C(N(CC)C1C=CC=CC=1)C>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[Cl:13]
Reactant: O=[N+]([O-])c1cncc(Br)c1O
Reactant: ClP(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: O=[N+]([O-])c1cncc(Br)c1Cl
Reaction time: 2 h

Procedure:
3-bromo-5-nitropyridin-4-ol (49.8 g, 0.227 mol) prepared in Step 1 was slowly added at 0° C. to 200 ml of phosphorus trichloride. N,N-diethylaniline (34.65 ml, 0.227 mol) was slowly added thereto at the same temperature. The reaction mixture was refluxed under stirring for 2 hours and then concentrated under reduced pressure. The resulting residue was added to ice water and then extracted with 300 ml of ether. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 32.4 g of the titled compound as a pale yellow solid. The product was used in the subsequent step without further purification.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([F:18])[C:16]=3[CH:17]=[C:9]2[C:8]2[N:19]=[C:20]([C:23]3[C:24]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:25][C:26]4[O:30][C:29]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[C:28]([C:38]([NH:40][CH3:41])=[O:39])[C:27]=4[CH:42]=3)[CH:21]=[CH:22][C:7]=2[O:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([F:18])[C:16]=3[CH:17]=[C:9]2[C:8]2[N:19]=[C:20]([C:23]3[C:24]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:45])=[O:46])=[CH:25][C:26]4[O:30][C:29]([C:31]5[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=5)=[C:28]([C:38]([NH:40][CH3:41])=[O:39])[C:27]=4[CH:42]=3)[CH:21]=[CH:22][C:7]=2[O:6]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN=[N+]=[N-])O4)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 5-(6-(azidomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (2.8 g, 4.1 mmol) in MeOH (25 mL) at room temperature, 5% wet Pd/C (300 mg) was added and stirred under hydrogen atmosphere (30 psi) overnight. The reaction mixture was filtered. The filtrate was concentrated and the resulting residue was purified using silica gel column chromatography (dichloromethane:MeOH=20:1) to provide racemic 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (1.5 g, yield: 62.5%). And after SFC separation, Compound 114 and 115 were obtained. Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase:60% ethanol (0.05% DEA) in CO2. Flow rate: 3 mL/min Wavelength: 220 nm. Compound 114: RT=0.605 min, Compound 115: RT=1.393 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=O)[CH3:13].Cl.[Li+].[OH-].C[CH2:19][O:20][C:21]([CH3:23])=[O:22].CCCCCC.[CH3:30][CH2:31][O:32][C:33](C)=O>O.CO>[CH3:19][O:20][C:21]([C:23]1[C:30]([CH2:31][O:32][CH3:33])=[N:1][C:2]2[C:3]([C:12]=1[CH3:13])=[CH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[O:22]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: COCc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OC
Temperature: 75 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
A mixture of 4.0 g (19.7 mmol) 1-(2-amino-4-(trifluoromethyl)phenyl)ethanone, 11.5 ml (98.5 mmol) 4-chloro-diacetic acid ethyl ester and 1.7 ml (19.7 mmol) conc. hydrochloric acid was heated to 75° C. for 6 min in a sealed vessel by microwaves (50 W). The mixture was subsequently diluted with EtOAc and water. The organic phase was separated, washed with a 1M aq. NaHCO3 sol., dried over MgSO4 and concentrated in a vacuum. The raw product (7.47 g) obtained after CC (EtOAc/hexane 3:17) of the residue was dissolved in MeOH (76 ml) and 35.3 ml (70.6 mmol) of a 2M aq. LiOH sol. was added. The mixture was subsequently stirred for 16 h at RT and heated to 60° C. for a further 24 h. After cooling to RT, the mixture was diluted with water and EtOAc. The organic phase was separated, dried over MgSO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:3) of the residue, 985 mg (3.1 mmol, 16%) 2-(methoxymethyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid methyl ester was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([O:38][C:39]1[CH:44]=[C:43]([CH2:45]Cl)[CH:42]=[CH:41][C:40]=1[Cl:47])[CH:36]=[CH2:37]>>[CH2:35]([O:38][C:39]1[CH:44]=[C:43]([CH:42]=[CH:41][C:40]=1[Cl:47])[CH2:45][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH:36]=[CH2:37]
Reactant: C=CCOc1cc(CCl)ccc1Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl

Procedure:
Analogously to Method D, 2.00 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 2-allyloxy-1-chloro-4-chloromethylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.18 (1:4 EtOAc-heptane); Rt=6.44.