Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([CH3:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1>[Pd].CCO.C(Cl)Cl>[NH2:26][C:24]1[CH:23]=[C:22]([CH3:29])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 6 h

Procedure:
A mixture of the title C compound, 4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluoro-benzenesulfonyl)phenol (0.69 g, 1.65 mmol) and palladium on activated carbon (10 wt. %; 69 mg) in 10 mL of EtOH and 10 mL of CH2Cl2 is stirred under hydrogen atmosphere (H2, 1 atm) for 6 h. The catalyst is removed by vacuum filtration through celite, washed with a 1/1-mixture of EtOH and CH2Cl2, and the combined filtrate and washings are concentrated and dried under vacuum to give 4-(4-amino-2,6-dimethylphenoxy)-2-(4-fluorobenzenesulfonyl)phenol: NMR (DMSO-d6) 1.93 (s, 6H), 4.92 (s, 2H), 6.34 (s, 2H), 6.85 (d, 1H, J=9), 7.00 (dd, 1H, J=9, 3), 7.12 (d, 1H, J=3), 7.43 (app t, 2H, J=9), 7.94 (dd, 2H, J=9, 5), 9.41 (s, 1H), 10.4 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][CH2:8][S:9][CH2:10][CH3:11])[NH2:6])[CH3:2].[C:13]([S:16][CH2:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20])(=[O:15])[CH3:14]>CO>[CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][CH2:8][S:9][CH2:10][CH3:11])[NH:6][C:19](=[O:20])[CH:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][S:16][C:13](=[O:15])[CH3:14])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)CCSCC
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Solvent: CO
Product: CCOC(=O)[C@H](CCSCC)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React L-Ethionine ethyl ester (3.51 g) and 3-acetylthio-2-benzylpropionic acid (4.37 g) in a manner similar to that described in Example 1, Step 1 to give a yellow residue. Chromatograph the yellow residue on the Waters Prep 500 (2 silica gel cartridges) and elute with ethyl acetate:hexane 2:18 (16L), then ethyl acetate:hexane 3:17. Repeat chromatography of the fractions using ethyl acetate:hexane as eluant to give Isomer A, a white solid (0.89 g), m.p. 84°-90°, [α]D26 =-60.6° (MeOH) and Isomer B (0.82 g), m.p. 79°-84°, [α]D26 =-0.3° (MeOH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1B(O)O>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][C:26]=5[O:25][CH3:24])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: COc1ccncc1B(O)O
Product: COc1ccncc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 28 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-methoxypyridin-3-ylboronic acid were reacted to give 266 (0.045 g, 28%). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=2.1, 1H), 8.50 (d, J=6.0, 2H), 7.92 (s, 1H), 7.46 (dd, J=8.3, 2.2, 1H), 7.15 (d, J=8.4, 1H), 6.93 (d, J=5.7, 1H), 5.84 (dt, J=13.3, 6.6, 1H), 4.46 (t, J=5.0, 2H), 3.91 (s, 3H), 3.45 (t, J=5.0, 2H), 1.59 (d, J=6.7, 6H). MS (ESI(+)): m/z 420.1 (M+H)
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1.[N+:21]([O-])([O-:23])=[O:22].[K+].C(=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C>[NH2:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22]
Reactant: COC(=O)c1ccc(N)c2c1OCCO2
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Concentrated sulphuric acid (6.5 ml) was treated cautiously with stirring at 5°-10° C. with glacial acetic acid (12 ml) and to the resulting solution was added methyl 8-amino-1,4-benzodioxan-5-carboxylate (1.5 g, 0.0072 mole). The mixture was stirred at room temperature for 1 h, then treated portionwise over 45 minutes with potassium nitrate (0.85 g, 0.0084 mole). The mixture was stirred for a further 4 h then poured into water (100 ml) and basified with potassium carbonate. A precipitate was produced and this was filtered off, washed with water and dried to afford methyl 8-amino-7-nitro-1,4-benzodioxan-5-carboxylate as a yellow solid (0.30 g). The filtrate was extracted with ethyl acetate and the extract dried (Na2SO4) and concentrated in vacuo to afford a further 1.1 g of the product as an orange solid. 1H NMR (CDCl3) δ:8.50(s,1 H), 6.0-7.0(v br,2 H), 4.30-4.55(m,4 H), 3.87(s,3 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 58.1 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (805 mg, 3.0 mmol) and 4-cyano-benzohydrazide (483 mg, 3.0 mmol) were coupled in a procedure analogous to that used for the preparation of inter mediate 3b. The crude product was purified by boiling in chloroform (10 mL) followed by cooling to 0° C. and filtration to yield product as a light yellow solid (718 mg, 50%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.85 (br s, 2H), 8.09 (AA′XX′, J=8.2 Hz, 2H), 7.92 (AA′XX′, J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.60 (d, J=7.3 Hz, 1H), 4.27 (m, 1H), 4.16 (dd, J=5.0, 7.3 Hz, 1H), 2.88 (br s, 1H), 2.34 (s, 3H), 1.39 (d, J=6.4 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C[O:30][C:31](=[O:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH2:39][CH2:40]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH:23]4[CH2:28][CH2:27][N:26]([CH2:40][CH2:39][O:38][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[C:31]([OH:42])=[O:30])[CH2:25][CH2:24]4)=[CH:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCCOc1ccc2c(c1)OCO2
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCCOc3ccc4c(c3)OCO4)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D), starting with 8.1 mmol of 1-[3-(benzo[1,3]dioxol-5-yloxy)-propyl]-3-piperidin-4-yl-1H-indole and 2.3 g (11 mmol) of of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After the standard work-up, 2.68 g of the corresponding acid was obtained. The crude mixture was purified by flash chromatography over silica gel affording 1.15 g (26% of yield) of the expected acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Agent: [Pt]
Solvent: CO
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
2.65 g of compound 8.1 (10 mmol) was suspended in MeOH (50 ml) and treated wet 5% Pt/C (Degussa type, Aldrich, 1.5 g). The flask is flushed with hydrogen gas from a balloon and the reaction mixture was stirred under hydrogen balloon for 2 hours. The reaction mixture was filtered through a Celite plug and the solvent is removed under reduced pressure to yield 2.0 g of the desired product.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]=[C:5]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1>CC(C)=O>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:41]#[C:40][CH2:39][N:24]2[CH:23]=[C:22]([C:9]3[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:11]4[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]([N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[N:6][C:7]=4[N:8]=3)[CH:26]=[N:25]2)=[CH:43][CH:44]=1
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CCCn1c(N2CCCC2)nc2nc(-c3cn[nH]c3)n(COCC[Si](C)(C)C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(N2CCCC2)nc2nc(-c3cnn(CC#Cc4ccc(F)cc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 80 °C
Yield: 17.4 %

Procedure:
A mixture of 1-Propyl-8-(1H-pyrazol-4-yl)-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.111 g, 0.25 mmol), potassium carbonate (0.052 g, 0.38 mmol), 1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.69 g, 0.33 mmol) was taken in acetone (10 ml). The reaction mixture was heated at 80° C. for 2 hours. The mixture was cooled to room temperature and filtered through sintered funnel, washed with acetone. Solvent was evaporated and the residue was purified by preparative TLC to obtain pure 8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.025 g, 22%) as colourless oil.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:19]=[C:18]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:17]=[CH:16][N:15]=1>>[Br:13][C:14]1[CH:19]=[C:18]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[CH:16][N:15]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1ccnc(Br)c1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccnc(Br)c1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 42.4 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (73.8 mL, 62.0 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (41.3 mL, 62.0 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then 3-(2-bromo-pyridin-4-yl)-N-methoxy-N-methyl-acrylamide (5.6 g, 20.7 mmol, in diethyl ether/tetrahydrofuran 30.0 mL/30.0 mL) prepared in Step 2 was added thereto at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, quenched with distilled water at room temperature, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 2.9 g of the titled compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O)(=O)C.[C:8]1([C:14]([CH:16]=O)=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH3:1][NH:2][N:3]=[CH:16][C:14](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: CNN
Solvent: CC(=O)O
Solvent: O
Product: CNN=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.8 %

Procedure:
A mixed solution of methylhydrazine (0.554 mL, 10.5 mmol)/acetic acid (1 mL)/water (7.6 mL) was added to phenylglyoxal (1.34 g, 10 mmol) in water (130 mL), and the mixture was stirred at room temperature for 20 hours. The reaction solution was extracted with chloroform, and the extract was dried, filtered, evaporated and dried by means of a vacuum pump to give oxo(phenyl)acetaldehyde methylhydrazone (1.44 g (crude), yield 89%) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH3:18][O:19][CH:20]([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[CH3:18][O:19][CH:20]([C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[O:25])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:22]
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: COC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)NC1C(=O)Nc2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in examples 65 and 66 to yield (−)-2-methoxy-N-(6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid,
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12OCC[O:22]1)(=[O:11])=[O:10].Cl[CH2:27][C:28]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:27][C:28]4([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:35][N:36]=[C:16]3[C:15](=[O:22])[C:14]=2[CH:13]=1)(=[O:10])=[O:11]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C(=O)N2
Reactant: N#CC1(CCl)CCCCCC1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC3(CCCCCC3)CN12

Procedure:
The title compound was prepared as a yellow foam from 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxolane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cycloheptanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/EtOAc (9:1). NMR (400 Mz, DMSO-d6): consistent. Analytical HPLC (Chromolith Monolith 0.46×10 cm column, gradient of acetonitrile in water/trifluoroacetic acid): 93.2% (254 nm). MS: (API-ES+) m/z 446.2 [M+H]; (API-ES−) m/z 444.2 [M−H].
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][C:22]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1C=CC=CC=1>[Br:1][CH2:21][C:22]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1CBr
Yield: 53 %

Procedure:
N-Bromosuccinimide (1.18 g, 6.63 mmol) and 2,2′-azobis(isobutyronitrile) (20 mg) were added to a solution of tert-butyl 2-methyl-5-(trifluoromethyl)benzoate (1.57 g, 6.03 mmol) obtained in Example (2-1) in benzene (25 ml) and the mixture was heated under reflux for 60 minutes. The temperature of the reaction mixture was returned to room temperature and the residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=8/1-6/1) to give tert-butyl 2-(bromomethyl)-5-(trifluoromethyl)benzoate as a white powder (1.08, yield: 53%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[CH3:9])[CH:5]=[C:4]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:3]=1.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]([N:8]([CH3:9])[C:6]2[CH:5]=[C:4]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:3]=[C:2]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:7]=2)[CH3:11])=[CH:13][CH:14]=1
Reactant: C[C@@H](c1ccc(F)cc1)N(C)c1cc(-c2cnn(C)c2)cc(Cl)n1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccc(F)cc1)N(C)c1cc(-c2cnn(C)c2)cc(Nc2cnccn2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
60 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine, 18 mg of 2-aminopyrazine, 16 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 24 mg of sodium t-butoxide and 9 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 60 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow oil. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 29 mg of the objective compound as pale yellow powder.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C([N:27]1[CH2:30][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])=[CH:34][N:33]=2)[CH2:28]1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:27]2[CH2:30][CH:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])=[CH:34][N:33]=3)[CH2:28]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: Fc1ccccc1-c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-nitrophenyl chloroformate (734 mg g, 3.64 mmol) was added to a stirred solution of 2-(1-Benzhydryl-azetidin-3-yloxy)-5-(2-fluoro-phenyl)-pyridine (996 mg, 2.43 mol) in dichloromethane (25 mL) at ambient temperature. The resulting solution was stirred at ambient temperature for 18 hr, diluted with dichloromethane (150 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (3×150 mL) then sat. sodium chloride solution (150 mL). The organic phase was dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by trituration with Methyl tertiary butyl ether (25 mL) to give after filtration a yellow solid (786 mg, 79%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:9]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: O=C1CCCN1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1ccc(F)cc1N1CCCC1=O
Temperature: 105 °C
Yield: 86.9 %

Procedure:
A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs2CO3 (2.28 g, 7.0 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) (0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2 dba3 was introduced and the reaction mixture heated at 105° C. for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.887 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07 (1H, ddd, J=2.5, 7.6, 8.6 Hz), 3.96 (2H, t, J=7.0 Hz), 2.62 (2H, t, J=8.1 Hz), 2.30-2.22 (2H, m); LCMS (+ESI, M+H+) m/z 205.
Reaction SMILES: [NH:1]([C:5]1[CH:34]=[CH:33][C:8]2[NH:9][C:10]([CH:12]([C:14]3[NH:15][C:16]4[CH2:21][CH2:20][N:19](C(OCC5C=CC=CC=5)=O)[CH2:18][C:17]=4[N:32]=3)[CH3:13])=[N:11][C:7]=2[CH:6]=1)[C:2]([NH2:4])=[NH:3].O1CCCC1>[Pd].CO>[NH:15]1[C:16]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[N:32]=[C:14]1[CH:12]([C:10]1[NH:9][C:8]2[CH:33]=[CH:34][C:5]([NH:1][C:2]([NH2:4])=[NH:3])=[CH:6][C:7]=2[N:11]=1)[CH3:13]
Reactant: CC(c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2)c1nc2cc(NC(=N)N)ccc2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1nc2c([nH]1)CCNC2)c1nc2cc(NC(=N)N)ccc2[nH]1
Yield: 96.7 %

Procedure:
A mixture comprising benzyl 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (1.0 g, 2.2 mmol), 10% palladium on carbon (0.5 g), tetrahydrofuran (50 mL) and methanol (50 mL) was hydrogenated at one atmosphere, filtered and concentrated in vacuo to provide N-{2-[1-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-2-yl)ethyl]-1H-benzoimidazol-5-yl)-guanidine (0.69 g, 97% yield); LRMS(ESI): Calculated for C16H20N8: 324.4; Found (MH+): 325.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@@H:34]([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@@H:34]([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: C[C@H](N)CO
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (S)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H34N6O5SF [(M+H)+] 525.2290, observed 525.2294.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([NH:14][S:15](=[O:21])(=[O:20])[NH:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[C:10]([F:22])[C:5]=1[C:6]([O:8]C)=[O:7].C1COCC1>CO>[F:3][C:4]1[C:13]([NH:14][S:15](=[O:20])(=[O:21])[NH:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[C:10]([F:22])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)OC)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaOH (1M, 3.20 mL, 3.20 mmol) was added to methyl 2,6-difluoro-3-(N-propylsulfamoylamino)benzoate (0.24 g, 0.80 mmol) in 2:1 THF:MeOH (3 mL). The solution was stirred at room temperature for 16 hours, and then the solution was stirred at 70° C. for 16 hours. The solution was concentrated under reduced pressure to about half volume and then washed with EtOAc. The pH was adjusted to about 5, and the mixture was extracted with EtOAc (3×5 mL). The organic layers were dried over sodium sulfate, decanted and concentrated to provide 2,6-difluoro-3-(N-propylsulfamoylamino)benzoic acid.