Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:12]=[C:11]([SH:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[CH:8][CH:9]=2)[N:4]=1.[OH-].[Na+].I[CH3:26]>C(O)(C)C>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:26])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1ccc2c(S)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.4 %

Procedure:
To a solution of 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazoline-4-thiol (243 mg, ˜0.75 mmol) in isopropanol (5 mL) was added 1N NaOH (1.13 mL, 1.13 mmol), and the mixture was stirred at rt for 5 min. Iodomethane (0.06 mL, 0.90 mmol) was then added and the mixture was stirred at room temperature for 5 min. The mixture was concentrated under reduced pressure to afford a yellow solid that was collected and washed with water and methanol to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-4-(methylthio)quinazoline as a light yellow solid (152 mg, 60%). (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 8.57-8.66 (m, 1H), 7.93-8.12 (m, 3H), 7.85 (s, 1H), 7.62-7.71 (m, 1H), 2.56 (s, 3H), 2.53 (s, 3H). LCMS (ESI) m/z 336 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:12]=3[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC(C)=CC=1C.[C:38]1([O:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[O:44]([C:45]([NH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:12]=3[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1nn(-c2cccc(N)c2)c2c1CS(=O)(=O)c1ccccc1-2
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(-c2cccc(NC(=O)Oc3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 1-(3-aminophenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide hydrochloride (100 mg, 0.243 mmol) in THF (10 mL) are added 2,4,6 collidine (0.06 mL, 0.487 mmol), phenylchloroformate (0.04 mL, 0.365 mmol) then stirred at RT for 18 h. After this time, reaction mixture is concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 100 mg of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:12])[N:4]=1.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22]O)=[CH:19][CH:18]=1)[CH3:15]>Cl>[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:12])[N:6]=2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: CNC1=NS(=O)N=C1NCCS
Agent: Cl
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
When 3-methylamino-4-(2p-mercaptoethylamino)-1,2,5-thiadiazole 1-oxide [prepared in Step A] is treated with about one equivalent of 5-dimethylaminomethyl-2-furanmethanol in concentrated hydrochloric acid according to the procedure described in Example 25, Step B, the title compound is thereby produced; identical to the product of Example 18.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][N:3]1[C:14]1[C:15](OS(C(F)(F)F)(=O)=O)=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)OB([C:48]2[CH:49]=[C:50]3[C:54](=[CH:55][CH:56]=2)[N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:52]=[CH:51]3)OC1(C)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:60]([O:59][C:57]([N:53]1[C:54]2[C:50](=[CH:49][C:48]([C:15]3[C:14]([N:3]4[CH2:4][CH2:5][N:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=5)[CH2:7][C@@H:2]4[CH3:1])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=4)[N:16]=3)=[CH:56][CH:55]=2)[CH:51]=[N:52]1)=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
To a solution of (S)-methyl 3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (240 mg, 0.38 mmol) in ethylene glycol dimethyl ether (20 ml) was added Pd(PPh3)4 (27 mg, 0.02 mmol), sodium carbonate (74.3 mg, 0.69 mmol) in water (6 ml), and tert-butyl 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (300 mg, 0.87 mmol). After stirring 90 minutes at 90° C. in an oil bath, the reaction was then quenched by the addition of water (200 ml), extracted with dichloromethane (3×30 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford a residue, which was purified via silica gel chromatography (20% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(1-(tert-butoxycarbonyl)-1H-indazol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (134 mg, 60%).
Reaction SMILES: C(N1CCN(C2C=[C:11]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[N:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:17])C=CC=2)CC1)C>C(Cl)Cl.CO>[NH:20]1[CH:19]=[CH:24][N:23]=[C:11]1[NH:15][C:16]([C:18]1[C:19]2[N:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[N:30][CH:29]=2)=[CH:26][CH:27]=1)=[O:17]
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ncc[nH]1)c1ccc(-c2cncc3ccccc23)c2nccnc12

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52) in Step 14.1. Title compound: ESI-MS: 367.0 [M+H]+; TLC: Rf=0.17 (DCM/MeOH, 95:5).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].[CH3:25][C:26]1([CH3:33])[O:30]C(CO)C[O:27]1>>[CH3:25][C:26]1([CH3:33])[O:30][CH:2]([CH2:1][O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:3][O:27]1
Reactant: CC1(C)OCC(CO)O1
Reactant: C=CCOc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Product: COc1ccc2c(OCC3COC(C)(C)O3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using solketal in place of allyl alcohol, the title compound was synthesized.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]2.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[N:57]=[C:56]([CH2:58]O)[CH:55]=[CH:54][N:53]=2)=[CH:47][CH:46]=1>C1COCC1.O>[Cl:44][C:45]1[CH:46]=[CH:47][C:48]([NH:51][C:52]2[N:57]=[C:56]([CH2:58][O:32][C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]4)[CH:55]=[CH:54][N:53]=2)=[CH:49][CH:50]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: OCc1ccnc(Nc2ccc(Cl)cc2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1ccc2cc(OCc3ccnc(Nc4ccc(Cl)cc4)n3)ccc2[nH]1
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
A solution of triphenylphosphine (0.145 g, 0.552 mmol) in THF (2.0 mL) was cooled to 0° C. under N2 and DEAD (0.087 mL, 0.552 mmol) was added dropwise. The mixture was stirred for 10 min, then 6-hydroxyquinolin-2(1H)-one (0.068 g, 0.424 mmol) was added. After stirring for 5 min, a solution of (2-((4-chlorophenyl)amino)pyrimidin-4-yl)methanol (0.1 g, 0.424 mmol) in THF (2.0 mL) was added. The reaction was stirred for 18 h at room temperature. The mixture was diluted with water and filtered. The beige filter cake was stirred in methanol and filtered to give 6-((2-(4-chlorophenylamino)pyrimidin-4-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.03 g, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (s, 1H), 9.91 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 7.95-7.72 (m, 3H), 7.44-7.16 (m, 5H), 6.98 (d, J=5.0 Hz, 1H), 6.51 (d, J=9.5 Hz, 1H), 5.16 (s, 2H). LCMS: R.T.=3.74; [M+H]+=379.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.Cl[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[N:14][C:16]([O:18][CH3:19])=[O:17])=[CH:4][N:3]=1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)N=C1SCCN1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (227 mg, 1.1 mmol) and methyl chloroformate (165 mg, 1.2 mmol) were dissolved in 20 ml of acetonitrile, into which, potassium carbonate (114 mg, 1 mmol) was added in portions and stirred at room temperature overnight. The reaction solution was made free of solids, and the solids were washed with ethyl acetate, and from the wash the solvent was distilled off, and the resultant intended substance was recrystallized from ethyl acetate. Yield: 120 mg (42%). Melting point: 128-130° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O:16][C:17](=O)[CH:18]([O:25][CH3:26])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])C>C(O)(=O)C>[OH:24][C:19]1([C:20]([F:21])([F:22])[F:23])[CH:18]([O:25][CH3:26])[C:17](=[O:16])[NH:13][C:10]2[NH:11][N:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[C:9]1=2
Reactant: Nc1cc(-c2cccc(F)c2)n[nH]1
Reactant: CCOC(=O)C(OC)C(=O)C(F)(F)F
Solvent: CC(=O)O
Product: COC1C(=O)Nc2[nH]nc(-c3ccccc3)c2C1(O)C(F)(F)F
Reaction time: 15 h
Yield: 45.2 %

Procedure:
5-Phenyl-2H-pyrazol-3-ylamine (i) (100 mg, 0.62 mmol) was dissolved in glacial acetic acid (1 mL), 4,4,4-Trifluoro-2-methoxy-3-oxo-butyric acid ethyl ester (95%, 0.17 mL, 0.92 mmol) was added at RT and stirring was continued for 15 h at 120° C. The mixture was evaporated to dryness and the isomeric mixture was directly purified by preparative HPLC (Agilent 1100 Series, Chromolith prep RP-18e, 100-25). A colorless solid (92 mg, 0.28 mmol, 46%) was obtained, characterized as compound (x).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:9]1[C:4]([Cl:3])=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[Cl:10]
Reactant: BrBr
Reactant: CC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c(Br)c(Cl)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
21.3 ml of bromine diluted in 82 ml of acetic acid are added over 6 hours to 84.86 g of N-(3,5-dichlorophenyl)acetamide and 34 g of sodium acetate in 420 ml of acetic acid. After 12 hours at room temperature, the reaction mixture is heated for 5 hours at 50° C. The solvents are evaporated off under reduced pressure. The residue obtained is recrystallized from isopropanol; m.p.=224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:13]1([C:19]([C:21]2[C:26]([F:27])=[CH:25][C:24](F)=[CH:23][C:22]=2[F:29])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([C:21]1[C:22]([F:29])=[CH:23][C:24]([O:8][C:6]2[CH:5]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:25][C:26]=1[F:27])(=[O:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: O=C(c1ccccc1)c1c(F)cc(F)cc1F
Product: O=C(O)Cc1cc(Cl)cc(Oc2cc(F)c(C(=O)c3ccccc3)c(F)c2)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1>>[F:8][C:7]1[C:2]([C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[F:9])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: O=[N+]([O-])c1ccc(F)c(-c2ncccc2F)c1

Procedure:
2-Bromo-3-fluoropyridine, prepared according to the procedure of Queguiner et al. in Tetrahedron, 1983, 39, 2009-21, was coupled with 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (as prepared in Example 2, part a)) by the method of Example 2, part b) to yield 3-fluoro-2-(2-fluoro-5-nitrophenyl)pyridine, which was transformed into 2-(5-bromo-2-fluorophenyl)-3-fluoropyridine by the method of Example 4, parts b) and c). This was converted into 4-fluoro-3-(3-fluoropyridin-2-yl)phenylboronic acid by the method of Example 5 part d), using bis(neopentyl glycolato)diboron instead of bis(pinacolato)diboron. δH (400 MHz, DMSO) 8.58 (1H, m), 8.19 (2H, s), 8.04 (1H, dd, J 8 and 2), 7.95 (1H, m), 7.86 (1H, m), 7.57 (1H, m), 7.31 (1H, dd, J 11 and 8).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[CH2:16][CH2:17][N:18]3[CH2:26][CH:25]4[CH2:27][CH:21]5[CH2:22][CH:23]([CH2:28][CH:19]3[CH2:20]5)[CH2:24]4)[CH2:7]1)[CH2:13]2>>[Cl:3][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[CH2:16][CH2:17][N:18]3[CH2:26][CH:25]4[CH2:27][CH:21]5[CH2:22][CH:23]([CH2:28][CH:19]3[CH2:20]5)[CH2:24]4)[CH2:7]1)[CH2:13]2
Reactant: OC12CC3CC(C1)C(CCN1CC4CC5CC(C4)CC1C5)C(C3)C2
Reactant: O=S(Cl)Cl
Product: ClC12CC3CC(C1)C(CCN1CC4CC5CC(C4)CC1C5)C(C3)C2

Procedure:
Thionyl chloride 5 ml was added to 4-[2-(5-hydroxy-2-adamantyl)-ethyl]-4-azatricyclo[4.3.1.1 3.8 ] undecane 105 mg obtained in example 8 and refluxed for 4 hours. Reaction mixture was concentrated in vacuo and saturated sodium bicarbonate was added to the residue to set to alkaline pH, then extracted with chloroform. The extract was dried by adding ahnydrous sodium sulfate. After removal of drying agent, the filtrate was concentrated in vacuo, and the residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: methanol=50:1-20:1) to obtain the product as a mixture of stereoisomer. (a mixture of stereoisomer 1:1 measured by gas chromatography)
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:19](N=[N+]=[N-])=[O:20].C(OC(C)C)(C)C>C1C=CC=CC=1>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:19](=[O:20])[C:18]2[CH:17]=[C:16]([O:15][CH3:14])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(C(=O)N=[N+]=[N-])cc(OC)c1OC
Reactant: NC1CCN(Cc2ccccc2)C1
Solvent: c1ccccc1
Solvent: CC(C)OC(C)C
Product: COc1cc(C(=O)NC2CCN(Cc3ccccc3)C2)cc(OC)c1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 1.8 g. (0.01 mole) of 3-amino-1-benzylpyrrolidine, 2.4 g. (0.01 mole) of 3,4,5-trimethoxybenzoyl azide, and 25 ml. of dry benzene was stirred 16 hours at room temperature followed by stirring for one hour at about 60°C. The mixture was cooled and 50 ml. of isopropyl ether added to the mixture. The crude crystalline product was separated by filtration and recrystallized from ethyl acetate-isopropyl ether mixture, giving 2.2 g. (60% yield). The melting point of the product after a second recrystallization from the same solvent was 128°-129°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][NH:55][CH3:56]>CS(C)=O.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([N:55]([CH3:56])[CH3:54])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:33]=[C:34]([C:42]([F:44])([F:43])[F:45])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=3)[C:28]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CNC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)N1c2ccc(N(C)C)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 40 °C
Reaction time: 72 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg) is dissolved in dimethylsulfoxide (2 ml), and thereto is added a 2M solution (300 μl) of dimethylamine in tetrahydrofuran under ice-cooling. The mixture is stirred at 40° C. for 72 hours in a closed vessel, and partitioned by adding water and ethyl acetate to the reaction solution. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-dimethylamino-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (78 mg). MS (m/z): 682 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:34]1([CH2:39][CH2:40][OH:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.[CH3:42][O:43][C:44]1[CH:49]=[C:48]([C:50]2[CH:51]=[C:52]3[C:58]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=4[O:65][CH3:66])=[CH:57][NH:56][C:53]3=[N:54][CH:55]=2)[CH:47]=[CH:46][C:45]=1O>C(Cl)Cl>[CH3:66][O:65][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[C:58]1[C:52]2[C:53](=[N:54][CH:55]=[C:50]([C:48]3[CH:47]=[CH:46][C:45]([O:41][CH2:40][CH2:39][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:44]([O:43][CH3:42])[CH:49]=3)[CH:51]=2)[NH:56][CH:57]=1
Reactant: OCCN1CCCC1
Reactant: COc1cc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)ccc1OCCN1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 15.9 %

Procedure:
To an 8 ml borosilicate reaction vial were added 150 mg (0.350 mmol) of PS-triphenylphosphine (2.33 mmol.g−1; Argonaut Technologies) and anhydrous methylene chloride (5 ml). The vial was fitted with a rubber septum and the suspension was stirred for 5 minutes in an ice-bath (0° C.). Diisopropyl azodicarboxylate (68 μL, 0.35 mmol) was added dropwise, and the mixture was allowed to warm to room temperature over 20 minutes. To the reaction vial was added 2-pyrrolidin-1-yl-ethanol (54 mg, 0.47 mmol) and 2-methoxy-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenol (60 mg, 0.17 mmol), and the suspension was stirred at room temperature for 8 hours. The yellow reaction mixture was filtered, and the resin was washed three times with DCM and ether, then twice with DCM. The combined filtrate was concentrated to obtain a yellow residue, which was purified by flash chromatography on amine functionalized silica gel (ISCO RediSep® amine column) using a gradient of ethyl acetate in hexanes to afford 12 mg (8%) of 3-(2-methoxy-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine as a light yellow powder. 1H-NMR (d6-DMSO) δ=11.87 (br.s, 1H), 8.51 (d, 1H), 8.18 (s, 1H), 8.11 (d, 1H), 7.70 (d, 1H), 7.57 (dd, 1H), 7.27 (m, 1H), 7.24 (d, 1H), 7.17 (dd, 1H), 7.12 (dd, 1H), 7.06 (s, 1H), 7.04 (m, 1H), 4.08 (t, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.82 (t, 2H), 2.55 (m, 4H), 1.69 (m, 4H); MS m/z: 444 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[O:35][CH3:36])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:33])[CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: COc1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(N(C)C)cc3OC)n1)c2OC
Yield: 65.3 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (64 mgs) and N(1)-(2,5-Dichloro-pyrimidin-4-yl)-2-methoxy-N(4),N(4)-dimethyl-benzene-1,4-diamine (77 mgs) were converted to the title compound (82 mgs) as a white solid. 1H-NMR (CDCl3, 400 MHz): 8.29 (d, J=8.2 Hz, 1H), 8.09-8.04 (m, 2H), 7.42 (s, 1H), 7.38 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.39-6.37 (m, 2H), 4.31-4.10 (broad absorption, 2H), 3.93 (s, 3H), 3.84 (s, 6H), 3.00-1.95 (broad absorption, 6H), 1.16 (t, J=7.0 Hz, 3H); LC/MS: found (M+H)+=511.46 MP: 190-193° C.;
Reaction SMILES: [Na:1].[SH:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:13]1[S:17](=[O:19])(=[O:18])[O:16][CH2:15][CH2:14]1>C(O)C>[Na:1].[S:17]([CH2:13][CH2:14][CH2:15][S:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5])([OH:19])(=[O:18])=[O:16]
Reactant: O=S1(=O)CCCO1
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Agent: [Na]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1SCCCS(=O)(=O)O
Reaction time: 1 h

Procedure:
In a mixture of 50 ml. of ethanol and 0.46 g. of metallic sodium were dissolved 3.4 g. of 2-mercapto-4-nitroaniline and 2.44 g. of propanesultone were added thereto under stirring. Thereafter, heating was conducted at 40°-50° C. for 1 hour and the crystalline substance thus separated was recovered by filtration, washed with ethanol and acetone and then dried to give 2 g. of the desired product. m.p. 181°-193° C.
Reaction SMILES: CC(C)(C)C([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=[N:24][N:23]=2)[CH:8]=1)=O>CO.O>[F:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][OH:5])=[CH:8][C:9]=1[C:22]1[N:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=[N:24][N:23]=1
Reactant: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2-c2nncn2C(C)C)c1
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(CO)cc2-c2nncn2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 213.5 %

Procedure:
To a room temperature solution of 29.4 (50 mg, 118 μmol) in MeOH (3.0 mL) was added LiOH monohydrate (1.0 M, 494 μL, 494 μmol). The mixture was stirred at room temperature for 30 minutes, diluted with water, and extracted with 30% IPA/chloroform. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-10% MeOH/DCM for elution gave 29.5 as colorless solid (86 mg, 89%)