Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[OH:16])/[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:6]=1.Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:15][O:16][CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[N:6]=1
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)/C(=N\O)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(=NOCC(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
6.1 g (25 mmol) of t-butyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dispersed in 250 ml of dry acetonitrile. 13.7 g (50 mmol) of p-nitrobenzyl bromoacetate and 12.9 ml (75 mmol) of N-ethyldiisopropylamine are now added thereto at room temperature while stirring. 7.5 g (50 mmol) of sodium iodide are added thereto 5 minutes later. The mixture is stirred at room temperature for 3.5 hours in an argon atmosphere. The solvent is subsequently removed by evaporation and the residue is diluted with 500 ml of ethyl acetate. The solution obtained is washed four times with a total of 2 l of water. The aqueous phase is extracted with 300 ml of ethyl acetate and the combined ethyl acetate solutions are dried over sodium sulphate and evaporated to dryness. After crystallization from ethyl acetate/hexane, there are obtained 8.2 g (75%) of t-butyl 2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxy]imino]-acetate of melting point 146.8° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCCCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 50.4 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 3-(4-nitrophenyl)propyl bromide (950 mg, 3.92 mmole), 520 mg (50% yield) of 5-[3-(4-nitrophenyl)-n-propyl]aminosalicylic acid was obtained as a pale yellow solid.: mp 229-231° C.
Reaction SMILES: [P:1](Cl)(Cl)[Cl:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[Cl-:2].[Cl-:2].[C:5]1([PH2:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccccc1
Reactant: ClP(Cl)Cl
Product: Pc1ccccc1
Product: [Cl-]

Procedure:
The reaction of a benzene with phosphorus trichloride to form a phenylphosphine dichloride involves reaction of one mole of the benzene with one mole of the phosphorus trichloride. Thus, the reaction may be carried out employing one mole of the benzene for each mole of phosphorus trichloride. However, it is preferred to employ an excess of the benzene over phosphorus trichloride. Thus, it is preferred to carry out the reaction employing a molar ratio of the benzene to phosphorus trichloride of 3:1 to 10:1.
Reaction SMILES: [Na].N.[NH2:3][CH2:4][C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:7]([CH3:21])[CH2:6]1.[CH3:22]I>CCOCC.C(O)C>[NH2:3][CH2:4][C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[N:12]([CH3:22])[CH:11]=3)[N:7]([CH3:21])[CH2:6]1
Reactant: CI
Reactant: CN1C[C@H](CN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: N
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CN1C[C@H](CN)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21

Procedure:
A mixture of 8 ml. of dry ethanol and 10 ml. of dry ether is added dropwise, within 20 minutes to the stirred solution of 1.9 g. of metallic sodium in 300 ml. of liquid ammonia. Upon this procedure the initially deep blue solution turns gradually colorless. Thereafter 2.53 g. of dried 8β-aminomethyl-6-methyl-ergoline, prepared as described in Step B above, are added, the mixture is stirred until complete dissolution occurs (for 5 minutes), and then a solution of 6.6 g. of methyl iodide in 8 ml. of dry ether is added dropwise, within 5 minutes to the mixture at -40° C. The mixture is stirred at the same temperature for an additional 30 minutes, thereafter it is warmed cautiously and ammonia is removed in vacuo. The residue is dissolved in a mixture of 100 ml. of isopropanol and 400 ml. of chloroform, 150 ml. of water are added to the solution, and the pH of the aqueous phase is adjusted to 8 with acetic acid. The mixture is shaken, the organic phase is separated, and the aqueous phase is extracted with 3×100 ml. of a 1:4 mixture of isopropanol and chloroform. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is subjected to chromatography using a column filled with 40 g. of silica gel in order to remove the impurities optionally present. A 30:2:11 mixture of chloroform, water and methanol is used as eluting agent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[N:29]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)n1

Procedure:
Example 76 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.0 Hz), 7.83 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.38–7.33 (m, 4H), 6.89 (d, 1H, J=7.6 Hz), 5.68 (br s, 1H), 3.26 (dd, 2H, J=6.0, 12.4 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.58–2.52 (m, 2H), 2.31 (t, 2H, J=6.8 Hz), 1.99 (t, 2H, J=12.0 Hz), 1.85 (d, 2H, J=12.8 Hz), 1.70–1.59 (m, 6H), 1.28 (d, 6H, J=6.8 Hz), 1.01 (dd, 2H, J=3.6, 6.4 Hz); ESMS m/e: 483.3 (M+H)+.
Reaction SMILES: [O:1]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])=[N:14][CH:15]=1)[Si](C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1.CCOC(C)=O>[OH:1][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])=[N:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccccc2C#N)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A mixture of 2-[5-(tert-butyldimethylsiloxymethyl)pyridin-2-yl]benzonitrile (4.9 g, 0.021 mol) and nBu4NF hydrate (8.1 g, 0.031 mol) in THF (60 mL) was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated to give 3.5 g (80%) of product as a brown solid, mp 152°-153° C.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][O:11][C:12]2[N:17]=[CH:16][C:15]([S:18]([NH:21][C:22](=[O:61])[C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]5[CH2:41][CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][C:37]=5[C:44]5[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=5)[CH2:31][CH2:30]4)=[CH:25][C:24]=3[O:51][C:52]3[CH:60]=[CH:59][CH:58]=[C:57]4[C:53]=3[CH:54]=[N:55][NH:56]4)(=[O:20])=[O:19])=[CH:14][C:13]=2[Cl:62])[CH2:6][CH2:5]1)(=O)[NH2:2]>O1CCOCC1.N1C=CC=CC=1>[Cl:62][C:13]1[CH:14]=[C:15]([S:18]([NH:21][C:22](=[O:61])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][N:32]([CH2:35][C:36]4[CH2:41][CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][C:37]=4[C:44]4[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=4)[CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:51][C:52]2[CH:60]=[CH:59][CH:58]=[C:57]3[C:53]=2[CH:54]=[N:55][NH:56]3)(=[O:20])=[O:19])[CH:16]=[N:17][C:12]=1[O:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([C:1]#[N:2])[CH2:5][CH2:6]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4cnc(OC[C@H]5CC[C@H](C(N)=O)CC5)c(Cl)c4)c(Oc4cccc5[nH]ncc45)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4cnc(OC[C@H]5CC[C@H](C#N)CC5)c(Cl)c4)c(Oc4cccc5[nH]ncc45)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 483D (50 mg) in dioxane (12 mL) and pyridine (1.2 mL) was cooled in an ice-water bath. The mixture was slightly warmed by removing the ice bath and then trifluoroacetic acid (0.3 mL) was added. The reaction was stirred for 1 hour and quenched with methanol and aqueous NaOH. The resulting mixture was stirred for 1 hour and concentrated. The residue was purified by reverse phase HPLC, and eluted with 40%-70% acetonitrile in 0.1% trifluoroacetic acid water over 40 minutes. The desired fractions were concentrated to remove acetonitrile, neutralized with NaHCO3 and extracted with dichloromethane. The dichloromethane layer was dried over Na2SO4, filtered, concentrated and dried to provide the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 13.10 (s, 1H), 8.27 (d, 1H), 7.85 (d, 1H), 7.80 (s, 1H), 7.58 (d, 1H), 7.37 (d, 2H), 7.02-7.11 (m, 4H), 6.80 (dd, 1H), 6.54 (d, 1H), 6.14 (d, 1H), 4.19 (d, 2H), 3.22 (s, 4H), 2.97 (s, 2H), 2.59-2.71 (m, 1H), 2.41 (s, 2H), 2.18 (s, 2H), 2.05 (dd, 2H), 1.98 (s, 2H), 1.79-1.90 (m, 3H), 1.47-1.62 (m, 2H), 1.42 (t, 2H), 1.04-1.19 (m, 2H), 0.94 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[CH3:11][O:12][CH2:13][CH2:14]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:14][CH2:13][O:12][CH3:11])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: COCCBr
Product: COCCOc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and 2-methoxyethylbromide according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 3.24 (3H, s), 3.73-3.75 (2H, m), 4.16-4.18 (2H, m), 4.62 (2H, s), 6.87 (1H, d, J=1.6 Hz), 6.93 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.18 (1H, d, J=8.0 Hz).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].C[C:14](=[O:18])[O:15]CC>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[C:14]([OH:18])=[O:15]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccccc1C(F)(F)F
Product: O=C(O)C(O)c1ccccc1C(F)(F)F

Procedure:
The 2-trifluoromethylbenzaldehyde (43.9 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 39.1 g. (70.5%). EA, MS(FD).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.O.[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([O:20][C:17]([C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1)=[CH2:18])[CH3:22]
Reactant: CCOC(C)=O
Reactant: COCCCn1ccc2ncc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cnc2ccn(CCCOC)c2c1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-1-(3-methoxypropyl)-1H-pyrrolo[3,2-b]pyridine (1.5 g) in toluene (30 mL) were added tri-n-butyltin-1-ethoxyvinyl (5.65 mL) and dichlorobis(triphenylphosphine)palladium (II) (782 mg), and the mixture was heated to stir at 110° C. for 30 minutes. The reaction solution was cooled to room temperature, and then thereto was added water-ethyl acetate, and an insoluble was filtered through Celite. The organic layer was separated, and then washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1→1/1) to give 6-(1-ethoxyvinyl)-1-(3-methoxypropyl)-1H-pyrrolo[3,2-b]pyridine [REx(23-2)] (1.69 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:16]1[C:28]2[NH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[CH:25]1[C:26]2[N:27]([C:2]3[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COc1cc(C(=O)O)c(Br)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)c(-n2c3ccccc3c3ccccc32)cc1C(=O)O
Yield: 50 %

Procedure:
Into a three-neck flask, 10 g (3.6×10−2 mol) of 2-bromo-5-methoxyterephthalic acid prepared in the above step (2), 12.04 g (7×10−2 mmol, 2 eq) of carbazole, 12.94 g (9.4×10−2 mmol, 1.3 eq) of K2CO3 and 0.3 g (3% w/w) of Cu were introduced and reacted in the presence of 300 ml of DMF for 48 hours, then cooled to room temeparature. The used solvent was distilled off under reduced pressure and the aqueous solution was washed with water and diethyl ether several times. To the aqueous solution so obtained, 5 N HCl was slowly added to produce yellow precipitates, which were then recrystallized with CHCl3. Yield: 50% (6.5 g); m.p.: 298° C.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.FC(F)(F)S([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2)(=O)=O.[CH3:39][O:40][N:41]([CH3:46])[C:42](=[O:45])[CH:43]=[CH2:44].C(N(CC)CC)C>CN(C=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH:32]1[C:33]2[C:29](=[CH:28][CH:36]=[C:35]([CH:44]=[CH:43][C:42]([N:41]([O:40][CH3:39])[CH3:46])=[O:45])[CH:34]=2)[CH:30]=[CH:31]1
Reactant: O=S(=O)(c1cccc2[nH]ccc12)C(F)(F)F
Reactant: C=CC(=O)N(C)OC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C=Cc1ccc2cc[nH]c2c1
Temperature: 120 °C
Yield: 39 %

Procedure:
Tris(dibenzylideneacetone) dipalladium (45 mg, 0.05 mmol) and tri-o-tolylphosphine (120 mg, 0.20 mmol) were stirred in DMF at room temperature for 30 min. The 4-trifluoromethanesulfonyl-1H-indole, N-methoxy-N-methyl acrylamide (1.26 g, 11.00 mmol), and triethylamine (2.20 g, 22.00 mmol) were added and the reaction was heated to 120° C. for 4 h. The reaction was allowed to cool and the solvent removed in vacuo. The residue was taken up in methylene chloride, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give a brown solid. The solid was purified by flash chromatography (EtOAc, hexanes) to give 3-(1H-indol-6-yl)-N-methoxy-N-methyl-acrylamide (0.90 g, 39% yield for the three reactions). 1H NMR (CDCl3): δ8.385 (bs, 1H), 7.86 (d, J=18.6 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.57 (s, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.25 (m, 1H), 7.03 (d, J=18.6 Hz, 1H), 6.55 (m, 1H), 3.78 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>C1COCC1.C(OCC)(=O)C>[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([NH:4][CH2:3][CH2:1][OH:2])=[O:9]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of ethanolamine (1.10 g, 15.8 mmol) in THF at 0° C. under N2 was added 2,4-difluorobenzoyl chloride (500 mg, 2.83 mmol). The reaction mixture was stirred at 0° C. for 4 h, then diluted with ethyl acetate (100 mL) and washed with 1 N HCl (50 mL), saturated NaHCO3 (50 mL), and saturated NaCl (50 mL). The organic solution was dried over MgSO4 and concentrated in vacuo to yield 2,4-difluoro-N-(2-hydroxyethyl)benzamide as a white solid (495 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[CH3:13][O:14][CH2:15][CH2:16]Br>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:16][CH2:15][O:14][CH3:13])[C:7]=12
Reactant: COCCBr
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Product: COCCn1c(C)c(C)c2ccnc(Cl)c21
Yield: 80 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 2-bromoethyl methyl ether, the titled compound was obtained as a white solid. (Yield: 80%)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH:9]=[C:8]([C:11]3[C:15]4[CH:16]=[N:17][C:18]([NH2:32])=[C:19]([O:20][C@@H:21]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=5[Cl:31])[CH3:22])[C:14]=4[O:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:2]1.C[Si]([N:37]=[C:38]=[O:39])(C)C.CN(C=O)C.CCN(C(C)C)C(C)C.N>CO>[NH2:32][C:18]1[N:17]=[CH:16][C:15]2[C:11]([C:8]3[CH2:7][CH2:6][N:5]([CH:3]4[CH2:2][N:1]([C:38]([NH2:37])=[O:39])[CH2:4]4)[CH2:10][CH:9]=3)=[CH:12][O:13][C:14]=2[C:19]=1[O:20][C@@H:21]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[Cl:31])[CH3:22]
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C4CNC4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C4CN(C(N)=O)C4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1-Azetidin-3-yl-1,2,3,6-tetrahydropyridin-4-yl)-7-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0209 mmol), trimethylsilyl isocyanate (4.25 μL, 0.0314 mmol), DMF (1.0 mL, 13 mmol) and DIPEA (7.30 μL, 0.0419 mmol) were mixed together and stirred at room temperature for 1 hour. The crude was passed through SCX-2 SPE and the product was release by 2 M NH3 in methanol for MDP purification. MS (ES+): m/z 555.05/557.04 (100/76) [MH+]. HPLC: tR=0.55 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=6.8 Hz, 3H), 2.56 (br. s., 2H), 2.67-2.73 (m, 2H), 3.15-3.22 (m, 2H), 3.34-3.42 (m, 1H), 3.89 (dd, J=8.6, 5.3 Hz, 2H), 4.01-4.09 (m, 2H), 6.27 (br. s., 1H), 6.50 (q, J=6.7 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H), 8.19 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:21])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C[CH2:37][O:38]C(C)=O>ClCCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:37]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][C:25]3[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=3)=[CH:30][CH:31]=2)=[O:38])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(Oc2ccncc2)cc1
Solvent: ClCCCl
Product: COCCOc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
To a solution of 5-tert-butyl-2-[4-(2-methoxyethoxy)phenyl]2H-pyrazol-3-ylamine (75 mg, 0.26 mmol) in anhydrous DCE (1.0 mL) was added CDT (37 mg, 0.31 mmol), and the reaction mixture was stirred at 60° C. for 6 h. A solution of 4-(pyridin-4-yloxy)phenylamine (48 mg, 0.26 mmol) in DCE (1.3 mL) was then added, and the mixture was stirred at 60° C. for 20 h. The reaction mixture was diluted into EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude product was purified by HPLC and recrystallized from ether/DCM/hexane to give 45.2 mg (35%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.01 (s, 1H), 8.39 (d, J=4.8 Hz, 2H), 8.28 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 4H), 6.84 (d, J=4.8 Hz, 2H), 6.29 (s, 1H), 4.14 to 4.10 (m, 2H), 3.66 to 3.63 (m, 2H), 3.28 (s, 3H), 1.23 (s, 9H); MS LC-MS [M+H]+=502, RT=2.80 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[CH:25]=1>>[Cl:30][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:3]=[CH:4][C:5]([C:18]3[CH:19]=[N:14][CH:15]=[N:16][CH:17]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1cncnc1
Reactant: Nc1ccnc(Cl)c1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1ccc2c(-c3cncnc3)cnc(Nc3ccnc(Cl)c3)c2n1

Procedure:
The title compound, MS: m/e=349.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 5-pyrimidineboronic acid and 4-amino-2-chloropyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:7][NH:6]1)=[O:4].[H][H].[CH3:20]O>C=O.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:7][N:6]1[CH3:20])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1
Reactant: CO
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C

Procedure:
To a solution of 800 mg of (2S, 4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carboxylic acid methyl ester in 8 mL of methanol, 0.35 mL of 37% formalin and 80 mg of 10% palladium on carbon were added, and stirred at 4 atm. Hydrogen pressure for 10 hours. After filtering out the catalyst, the solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:6), to afford 489 mg of the title compound as a colorless oil.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].[CH2:23]([NH:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:24]([CH3:26])[CH3:25]>C1COCC1>[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)CNCC(C)C
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)CN(CC(C)C)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Diisopropylcarbodiimide (13.8 ml, 1.2 eq) is added to 4-fluoro-3-nitrobenzoic acid (15 g, 1 eq) in solution in THF (150 ml). The mixture is stirred for 3 hours at a temperature of approximately 20° C. then diisobutylamine (12.9 ml, 1 eq) is added. After stirring for 15 hours at approximately 20° C., the reaction mixture is evaporated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (70 ml). After decantation and extraction, the combined organic phases are washed with salt water, followed by drying over Na2SO4 then evaporating under reduced pressure at 40° C. Purification of the compound by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2) produces the expected compound in the form of a yellow solid (13.8 g; 63% yield).