Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH:5]([NH:24]C(=O)OC(C)(C)C)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([CH3:22])[C:12]=2[CH:23]=1.Cl.O1CCOCC1>C(OCC)C>[NH2:24][CH:5]([CH2:4][CH2:3][C:2]([F:32])([F:33])[F:1])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([CH3:22])[C:12]=2[CH:23]=1
Reactant: Cn1c(=O)c2cnccc2c2ccc(OCC(CCC(F)(F)F)NC(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1c(=O)c2cnccc2c2ccc(OCC(N)CCC(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl (5,5,5-trifluoro-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (150 mg, 0.322 mmol) in diethyl ether (10 mL) under nitrogen atmosphere, cooled to 0° C. was added 4M HCl in 1,4-dioxane (0.098 mL, 0.392 mmol) slowly over a period of 5 min. The light yellow reaction mixture was stirred at 0° C. for 5 min then warmed to room temperature and allowed to stir for 12 h. The solvent was removed under reduced pressure. The residual yellow oil was diluted with water (3 mL) and extracted with EtOAc (2×4 mL). The aqueous layer was separated and treated with sat. Na2CO3 solution (3 mL). The resultant aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layer s were separated and washed with water (2×5 mL), brine (1×5 mL) and dried over sodium sulfate. The filtrate was evaporated under reduced pressure and purified by SFC (CO2 and 0.5% DEA in Methanol) to afford 8-((2-amino-5,5,5-trifluoropentyl)oxy)-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (102.8 mg, 0.278 mmol, 86% yield) as a white solid. LC/MS (ESI) m/e 366.2 [(M+H)+, calcd for C18H19F3N3O2366.13]; LC/MS retention time (method C): tR=1.77 min; HPLC retention time (method A): tR=7.79 min; HPLC retention time (method B): tR=8.20 min. 1H NMR (400 MHz, MeOD) δ 9.48 (d, J=0.80 Hz, 1H), 8.78 (d, J=5.60 Hz, 1H), 8.44 (d, J=8.80 Hz, 1H), 8.27 (d, J=5.60 Hz, 1H), 7.17 (d, J=2.40 Hz, 1H), 7.12 (dd, J=2.40, 8.80 Hz, 1H), 4.17-4.20 (m, 1H), 4.09 (dd, J=6.00, 9.40 Hz, 1H), 3.82 (s, 3H), 3.28-3.28 (m, 1H), 2.33-2.49 (m, 2H), 1.92-1.99 (m, 1H), 1.73-1.80 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:7]2[O:8][C@@H:6]2[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.C(C1C=C[C:21]2[O:26][C:25](C)(C)[C@H:24](O)[C@@H:23]([N:30](CC(OCC)=O)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]=2C=1)#N>CO>[O:26]1[CH:21]=[CH:22][C:24]([CH2:23][N:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:6]2[C:5]3[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=3[O:3][C:2]([CH3:15])([CH3:1])[C@@H:7]2[OH:8])=[CH:25]1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@H](N(Cc2ccoc2)c2ccccc2)[C@H]1O

Procedure:
The title compound was prepared from (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (the title A compound of Example 3) and the title A compound by the same procedure as described for the title compound of Example 1. The product was obtained as a colorless solid (0.85 g, 57%), mp 63°-67° C. [α]D =+65.2° (c=0.71 MeOH). Analysis calculated for C23H22N2O3 ·0.25H2O: C, 72.90; H, 5.98; N, 7.39. Found: C, 72.94; H, 5.95; N, 7.35.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg) in DMF (2.0 ml) was added at 22° C. NaH (55% in oil, 64 mg) and stirring was continued until gas evolution ceased. The suspension was cooled to 0° C. and treated with trifluoroethyl trifluormethane sulphonate (728 mg) and stirring was continued at 22° C. for 2 h. The mixture was partitioned between saturated NaHCO3 and ethyl acetate and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using n-heptane/ethyl acetate (3:1) to give 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg) as a white solid. MS (ISP): m/z=236.3 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>>[OH:1][C@H:2]1[CH2:6][N:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1c1ccccc1[N+](=O)[O-]
Yield: 71.1 %

Procedure:
The same procedures used in Reference Example 1 were repeated except for using trans-4-hydroxy-L-proline and 1-fluoro-2-nitrobenzene to give the title compound. Yield 71.1%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].C([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=O)C>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:25][CH2:24][CH2:23][CH2:22][OH:21])[CH:10]=1)=[O:8]
Reactant: CC(=O)OCCCCBr
Reactant: O=C(Nc1nccs1)c1c[nH]c2ccccc12
Product: O=C(Nc1nccs1)c1cn(CCCCO)c2ccccc12

Procedure:
The title compound was prepared using 1H-indole-3-carboxylic acid thiazol-2-ylamide and 4-bromobutyl acetate as R5X.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=2[CH3:12])[O:3]1.CO>[Pd].C1C=CC=CC=1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:2]2([CH3:1])[CH2:11][CH2:10][C:9]3[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=3[CH3:12])[O:3]2)=[CH:19][CH:20]=1
Reactant: Cc1c(C)c(C)c2c(c1C)C=CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: Cc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2
Yield: 74.3 %

Procedure:
Following a procedure similar to that described in Preparation 4, 760 mg of 2,5,6,7,8-pentamethyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 31) were hydrogenated, using 100 mg of 10% w/w palladium-on-carbon, 20 ml of methanol and 70 ml of benzene, at atmospheric pressure, to afford 520 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=1[OH:18])(=[O:7])=[O:6])([CH3:3])[CH3:2].[H][H]>[Pd]>[CH:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[OH:18])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)NS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 98.4 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-isopropyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.7 g, 2.38 mmol) was reduced with hydrogen and Pd/C (0.7 g) to form the desired product (0.62 g, 98 %). EI-MS m/z 263.5 (M-H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.CC1[N:20]=CC(COP(O)(O)=O)=C(C=O)C=1O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:20])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)CC(N)CC2

Procedure:
Into a flask in which substrates, that is, 300 mg of 7-methoxy-2-tetralone and 309.4 mg of (S)-α-phenethylamine were added in advance, 3 ml of the cell-dispersion solution, 3.7 mg of pyridoxal phosphate, and 3 mL of a 1M potassium phosphate buffer (pH 6.8) were introduced. The whole volume was adjusted to 30 mL by adding deionized water therein. This was reacted at 30° C. for 24 hours with stirring. After the reaction is completed, 7-methoxy-2-aminotetralin thus produced in the reaction mixture was analyzed by HPLC with the conditions described below. This showed that 7-methoxy-2-aminotetralin was produced with a conversion rate of 85%, and it had a (S) configuration and optical purity of 96.7% e.e.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[NH2:11].C(O[C:15]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=N)C>C(O)C>[F:8][C:7]1[C:2]2[N:1]=[C:15]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:11][C:3]=2[C:4]([F:10])=[C:5]([F:9])[CH:6]=1
Reactant: Nc1c(F)cc(F)c(F)c1N
Reactant: CCOC(=N)C(C)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(C)c1nc2c(F)cc(F)c(F)c2[nH]1
Yield: 42.6 %

Procedure:
A mixture of 1,2-diamino-3,4,6-trifluorobenzene (1.92 g, 11.8 mmol), ethyl 2-ethoxycarbonimidoylpropionate (3.1 g, 14.7 mmol) and absolute ethanol (6 ml) was heated at reflux until no further progression of the reaction was indicated by TLC indicated the reaction was not progressing further, filtered from NH4Cl and concentrated. The residue was purified by chromatography on silica (hexane: methylene chloride: ethyl acetate, 5:5:1) to give ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionate (1.37 g, 42%) as a tan crystalline solid; NMR (CDCl3): δ 10.35 (s, ½H), δ 7.05 (s, ½H), 6.7 (m, 1H), δ 4.25 (dd, 2H), δ 4.15 (dd, 1H), δ 1.73 (d, 3H), δ 1.31 (t, 3H); M+ 272.9 (calcd for C12H11F3N2O2: 272.23).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]3[CH2:16][CH2:15]3)[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([C@@H:12]([CH:14]3[CH2:15][CH2:16]3)[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1
Reactant: CC(C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Solvent: CCO
Solvent: CCCCCC
Product: C[C@H](C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Yield: 48.1 %

Procedure:
Racemic 3-amino-7-bromo-5-(1-cyclopropylethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Example 164 (1.12 g) was resolved by HPLC (column: CHIRALPAD AD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=800/200(v/v)) to give the title compound (539 mg) having a longer retention time.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:20])=[O:8]
Reactant: CC(C)NNC(=O)C1CCCCC1
Reactant: O=C(O)COc1ccc(F)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)C1CCCCC1)C(=O)COc1ccc(F)cc1Br
Yield: 74.6 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (249 mg, 1.0 mmol) and cyclohexane carboxylic acid N′-isopropyl-hydrazide (221 mg, 1.2 mmol) in DMF (10 ml) was treated with diisopropylethyl amine (0.44 mL, 2.5 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 700 mg, 1.5 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white solid (310 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Br:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:16][CH2:17][CH2:18][N:10]1[C:11]([C:13](=[O:15])[CH3:14])=[CH:12][C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])=[N:9]1
Reactant: BrCCBr
Reactant: CC(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(-n2c(C)ccc2C)nn1CCBr
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 150d (5.4 g, 1.0 eq., 26.6 mmol), 1,2-dibromoethane (20.0 g, 4.0 eq., 106.4 mmol), K2CO3 (7.34 g, 2.0 eq., 53.2 mmol), and acetonitrile (100 mL). The reaction mixture was reflux for 5 hrs. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 6:1 petroleum ether/ethyl acetate to afford 150e (7.5 g, 91%) as a colorless oil. MS-ESI: [M+H]+ 309.9
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH:13]1[CH:14]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2c[nH]cn2)cc1
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A suspension of 4-(4-nitro-phenyl)-1H-imidazole (50 g, 0.2646 mol), 5% Pd/C (6 g) in 600 mL of methanol is hydrogenated at 7 psi of hydrogen at room temperature. After 1 h, the pressure of hydrogen remained unchanged, the mixture is filtered through a Celite cake. The filtrate is evaporated to give a red residue. After drying at high vacuum overnight, 43.2 g of a beige foam is isolated. It is hydroscopic, and sensitive to light and air.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.C1CCN2C(=NCCC2)CC1.[CH2:31]([OH:33])[CH3:32]>>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:33][CH2:31][CH3:32])[N:3]=1
Reactant: CCO
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)n2nc(-c3ccco3)nc2n1

Procedure:
A solution of 7-amino-2-(2-furyl)-5-methylsulphonyl[1,2,4]triazolo[1,5-a][1,3,5]triazine (1.6 g) in ethanol (40 ml) containing DBU (1.0 ml) was heated under reflux until no starting material remained by TLC analysis. The solvent was removed by evaporation and the residue purified by chromatography on silica using 5-10% v/v ethyl acetate in dichloromethane as eluant, followed by crystallisation from ethanol to give 7-amino-5-ethoxy-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazine as hygroscopic crystals, m.p. 211°-213° C.; microanalysis, found: C, 48.7; H, 4.5; N, 31.4; H2O, 1.2%; C10H10N6O2. 0.33C2H5OH. 0.165H2O requires: C, 48.4; H, 4.7; N, 31.8; H2O, 1.1%; NMR: 1.05(t, 1H, CH3CH2OH), 1.35(t, 3H, CH3CH2), 3.4(q, CH3CH2OH), 4.3(q, 2H, CH3CH2O--), 6.7(dd, 1H, furyl-4H), 7.1(d, 1H, furyl-3H), 7.9(d, 1H, furyl-5H), 8.5-9.0(d, 2H, NH2); m/e 246 (M+).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>O>[C:6]1([CH3:12])[C:7]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O
Temperature: 65 °C
Reaction time: 5 h

Procedure:
560 g of 98% sulfuric acid was dropped into 560 g of toluene while stirring. Then, while the stirring was continued, the temperature was raised at 60 to 70° C., reacting for 5 hours. After the reaction, 500 g of distillation water was added. Then, 200 g of ether was added. The lower phase (water phase) of the two separated phases was taken, into which a step of distillation for condensation and addition of water was repeated twice, so as to obtain toluenesulfonic acid. As a result of analysis, the toluenesulfonic acid included the para compound thereof at a concentration of 85 mole % in the total of the toluenesulfonic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:8]1[CH:9]=[CH:10][C:3]2[C:2]([CH3:1])=[CH:6][S:5][C:4]=2[CH:7]=1)=[O:13]
Reactant: Cc1csc2cc(C(=O)O)ccc12
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2c(C)csc2c1

Procedure:
A solution of 3-methylbenzo[b]thiophene-6-carboxylic acid (3.65 g) in methanol (100 ml) was saturated with hydrogen chloride gas and the solution was heated under reflux for 4 hours, and then evaporated. The residue was dissolved in ether and the solution was washed with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave 3-methylbenzo[b]thiophene-6-carboxylic acid methyl ester (3.70 g) pure enough for further reaction. A sample crystallized from petrol (b.p. 40°-60°) had m.p. 46°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:27][CH:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])=[CH:31][N:30]=3)[CH2:25]2)=O)=CC=1)([O-])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH:9][C:22]([N:24]2[CH2:25][CH:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])=[CH:31][N:30]=3)[CH2:27]2)=[O:21])=[CH:5][CH:4]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Reactant: COc1ccc(N)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N2CC(Oc3ccc(-c4ccccc4F)cn3)C2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
To a solution of 6-Methoxy-pyridazin-3-ylamine (39 mg, 0.31 mmol, [Cas. No. 7252-84-8]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by flash chromatography (ethyl acetate) to give the title compound (35 mg, 37%)
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23].C(Cl)Cl>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:12]4[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:21])=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccc(S(C)(=O)=O)cc2)n1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(=O)[nH]c34)cc2F)n(-c2ccc(S(C)(=O)=O)cc2)n1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione (58 mg, 101 μmol) and a 0.06 M solution of 3-tert-butyl-5-isocyanato-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole in CH2Cl2 (6.8 mL, 0.41 mmol). The title compound was obtained as a white solid. Yield: 30 mg (49%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>CN(C)C(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3=[N:20][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:16]3[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 60 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
A solution of 3-(4-phenoxyphenyl)pyridin-2-amine (301 mg) in N,N-dimethylacetoamide (3 mL) was added dropwise to 2-chloroethanesulfonyl chloride (382 mg) and additional N,N-dimethylacetoamide (2 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 4 hr, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and THF (3 mL), and dried in vacuo at 60° C. to give the title compound (346.7 mg) as an off-white powder.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][N:17]2[C:21]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([N+:30]([O-:32])=[O:31])[C:19](Br)=[N:18]2)[N:12]=[C:11](Br)[C:10]=1[N+:35]([O-:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1(OB(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][N:17]2[C:21]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([N+:30]([O-:32])=[O:31])[C:19]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:18]2)[N:12]=[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[N+:35]([O-:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccccc1
Reactant: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1c(-c2ccccc2)nn(CCCn2nc(-c3ccccc3)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1
Yield: 81.8 %

Procedure:
3.7 g of 1,3-bis-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propane from step 5.2 in 40 ml 1,2-dimethoxyethane are mixed under nitrogen with 3.8 g phenyl boric acid, 1.2 g of tetrakis(triphenylphosphin)palladium (0) and a solution of 8.3 g of potassium carbonate in 30 ml water. The resulting reaction mixture is subsequently heated under reflux under nitrogen. After five hours the reaction mixture is heated over silica gel (hyflo super-gel of Celite Co.), filtered and the filtrate cooled in an ice bath. The precipitate coming down is filtered, washed with water and recrystallized from 50 ml ethanol. After drying in vacuum at 60° C. one obtains 1.5 g of a yellow product.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][C:17](=O)[CH3:18])[CH:11]=3)=[CH:6][C:5]=12.Cl.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>CO>[N:21]1([CH:17]([CH3:18])[CH2:16][C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=3)[CH:15]=[CH:14][N:13]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(=O)Cc1cc(-c2ccn3ccnc3c2)ccn1
Reactant: C1COCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(Cc1cc(-c2ccn3ccnc3c2)ccn1)N1CCOCC1
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Dissolve 1-(4-imidazo[1,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-one (3.9 g, 15.5 mmol) in methanol (400 mL) under nitrogen. Add morpholine hydrochloride (38.4 g, 20 equiv.) followed by 3 {acute over (Å)} Sieves (7.8 g, powdered and dried in a vacuum oven at 100° C. overnight). Stir five minutes then add sodium cyanoborohydride (1.0 M in THF, 28 mL, 1.8 equiv.) via syringe and stir at room temperature for 5 days. Filter to remove insoluble material, washing with methanol. Concentrate to dryness then make basic with 20% NaOH (aq) and extract with ethyl acetate. Wash organics with aqueous saturated sodium chloride then dry over MgSO4. Filter and concentrate then purify by silica gel (Ethyl Acetate→5% Methanol:DCM→10% Methanol:DCM→5% 2M NH3 in methanol:DCM→10% 2 M NH3 in Methanol:DCM) to give product as a tan solid (3.7 g, 74%). MS (ES), m/z 323 (M+1).