Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:11][CH:12]=[CH2:13])=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.CC(N=NC(C#N)(C)C)(C#N)C.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(=O)(O)[O-].[Na+]>[OH:1][C:2]1[C:3]([CH2:11][CH2:12][CH2:13][S:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: C=CCc1cc2c(cc1O)CCS2
Reactant: Sc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cc2c(cc1CCCSc1ccccc1)SCC2
Temperature: 90 °C

Procedure:
To a solution of 5-hydroxy-6-allyl-2,3-dihydrobenzothiophene (125 mg, 0.65 mmole) in 0.5 mL thiophenol was added 28 mg AIBN. The reaction mixture was purged with nitrogen and heated to 90° C. for 3 hours. TLC analysis (90/10 hexane/EtOAc) showed the reaction to be complete. The reaction mixture was diluted with 25 mL saturated sodium bicarbonate and extracted 3×25 mL EtOAc. The combined organics were washed with sodium bicarbonate (2×25 mL), H2O (1×25 mL) and brine (1×25 mL). Drying over Na2SO4, filtration and concentration afforded 568 mg crude product as an oil. Purification by flash chromatography (90/10, hexane/EtOAc) 126 mg (64%) pure product NMR 287 MS181.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([C:13]#[N:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(OCC)O[CH2:24][CH3:25]>>[CH2:11]([O:10][CH:8]([CH:7]([CH2:6][C:5]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]#[N:14])[O:9][CH2:24][CH3:25])[CH3:12]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(C#N)Cc1cc(OC)c(OC)c(OC)c1
Product: CCOC(OCC)C(C#N)Cc1cc(OC)c(OC)c(OC)c1
Yield: 82 %

Procedure:
A solution of ethyl 3,4,5-trimethoxybenzylcyanoacetate (14.7 g) in triethyl orthoformate (100 ml) has heated at reflux for 18 hours using a steam-jacketed column for continuous removal of ethanol. The solution was cooled, and most of the excess orthoformate was removed in vacuo. The crystals obtained were washed with ether and dried to yield colourless crystals of α-carbethoxy-of diethoxymethyl-β-(3,4,5-trimethoxy phenyl)propionitrile (16.3 g, 82%), m.p. 91°; nmr (CDCl3) δ1.13, 1.20, and 1.32 (triplets, 9, CH3CH2O-), 3.15 (s, 2, Ar-CH2 -C), 3.4-4.0 (m, 4, m, 4, CH3CH2 -O), 3.85 (s, 9, -C6H2 -(OCH3)3), 4.13 (q, 2, CH3CH2 -OCO), 4.80 (s, 1, -CH (OEt)2), and 6.55 (s, 2, aromatic H).Anal. Calcd. for C20H29NO7 : C, 60.74; H, 7.39; N, 3.54. Found: C, 60.56; H, 7.33; N, 3.64.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1)[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24][CH3:25])[CH:17]=1)=O)(C)(C)C.F[C:40]([F:45])([F:44])C(O)=O.ClCCl>C(#N)C>[C:29]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=[C:27]([N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:40]([F:44])[F:45])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:28]=1
Reactant: COc1ccc(C(=O)N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)c2cccc(-c3ccccc3)c2)cc1OC
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(C(=O)N(C[C@@H]2CCCN2)c2cccc(-c3ccccc3)c2)ccc1OC(F)F

Procedure:
Experimental condition analogous to Example 1, from 1 g (1.94 mmol) of 2-(S)-{[biphenyl-3-yl-(3,4-dimethoxy-benzoyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 25 mL of trifluoroacetic acid and 100 mL of dichloromethane. Gave 0.75 gram of white semi solid: LC-MSD, m/z for: C26H26F2N2O3 [M+H]: 452.2. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 7 minutes: 3.54.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][N:24]=[C:25]=[O:26])[CH3:20].C(N(C(C)C)CC)(C)C>>[CH2:19]([O:21][C:22](=[O:27])[CH2:23][NH:24][C:25]([N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:14][CH2:15]1)=[O:26])[CH3:20]
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine (1.5 g, 5.7 mmol), isocyanato-acetic acid-ethy ester (0.7 mL, 6.3 mmol) and diisopropylethyl amine (1.5 mL, 8.6 mmol) are reacted to give [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid-ethyl ester the product as a white solid (990 mg, 40%). A mixture of the ester (990 mg), LiOH.H2O (1 g) in THF-H2O (5:1, 45 mL) was stirred at rt for 3 h, then acidified with 1.0 N HC (aq.) to pH to 4–5. After the removal of THF in vacuo, crude product precipitated. 760 mg (76%) of the acid was obtained after drying under vacuum for 3 h. LC-MS: 363 (M++1).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>COCCO>[F:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11]([OH:12])=[N:6][CH:5]=[N:7]2)=[CH:14][CH:15]=1
Reactant: N=CN
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CC(=O)O
Solvent: COCCO
Product: Oc1ncnc2cc(F)ccc12
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Formamidine acetate (20.13 g, 193.4 mmol) was added to a solution of 2-amino-4-fluorobenzoic acid (15 g, 96.7 mmol) in 2-methoxyethanol (97 ml) and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in aqueous ammonium hydroxide (0.01 M, 250 ml) for 1 hour. The suspension was filtered, washed with water and dried over phosphorus pentoxide to yield 7-fluoroquinazolin-4-ol as an off-white solid (10.35 g, 65% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH:14]4[CH2:15][CH2:16][O:17][C:5]34[C:4]=2[CH:3]=1.[H-].[Na+].[C:20]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CO>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:7](=[O:12])[CH:6]3[CH2:13][CH:14]4[CH2:15][CH2:16][O:17][C:5]34[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C23OCCC2CC13
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCN1C(=O)C2CC3CCOC32c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 9-chloro-3,3a,4,4a-tetrahydro-2H-furo[2′,3′:2,3]cyclobuta[1,2-c]quinolin-5(6H)-one (200 mg, 0.801 mmol) in dimethylformamide (4 ml) at 0° C. was slowly added sodium hydride (19 mg, 0.801 mmol) over 15 minutes. The suspension was allowed to warm to room temperature. The mixture stirred for 45 minutes and 4-(Boc-amino)butyl bromide (202 mg, 0.801 mmol) was added. The solution was stirred for 15 hours, followed by addition of 0.25 mL methanol. Column chromatography provided the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=2)O1>>[C:12]([C:6]1[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:34]3[CH:35]=[N:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=3)=[N:3]2)=[N:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cnc(C#N)nc3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclo-hexylamino}-1,5-naphthyridin-3-yl)ethanone (87 mg, 0.24 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (83 mg, 0.36 mmol) to afford the desired product (24 mg, 23%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.62 (s, 2H), 9.23 (s, 1H), 8.68 (d, J=8.9 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 5.52-5.41 (m, 1H), 3.12 (d, J=6.8 Hz, 2H), 2.94 (s, 6H), 2.77 (s, 3H), 2.51-2.42 (m, 2H), 2.08-1.94 (m, 3H), 1.88-1.65 (m, 2H), 1.37-1.25 (m, 2H); ESI MS m/z 430 [M+H]+; HPLC>99% (AUC), tR=8.73 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCNCC4)cc3)cn2)cn1
Reaction time: 18 h

Procedure:
4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (1.02 g, 2.0 mmol) was slurried in 1,4-dioxane/MeOH (5:1, 6 mL) and was treated with HCl (4M in 1,4-dioxane, 2 mL). After 18 hours, added more HCl (4M, 1,4-dioxane, 3 mL) and stirred 2 days. The solvents were removed via rotary evaporation and the crude was dried under vacuum to obtain the hydrochloride salt of the title compound as a sticky yellow solid which was used in the next step without further purification: MS (M+H)+399.4.
Reaction SMILES: C(O)(=O)C.Br[C:6]1[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[NH:14])=[N:8][CH:9]=[CH:10][CH:11]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:6]2[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[NH:14])=[N:8][CH:9]=[CH:10][CH:11]=2)=[CH:28][CH:27]=1
Reactant: COc1ccccc1CNC(=N)Nc1ncccc1Br
Reactant: OB(O)Oc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1CNC(=N)Nc1ncccc1-c1ccc(F)cc1
Temperature: 110 °C
Yield: 9.5 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.200 g (0.506 mmol) N-(3-bromopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine acetate, 0.106 g (0.759 mmol) (4-fluorophenyl)boric acid, 0.160 g (1.518 mmol) sodium carbonate, and 0.038 g (0.033 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 19 hr at 110° C. under a nitrogen atmosphere. Despite prolonging the reaction time to a total of 6 days and renewed addition of the starting materials sodium carbonate, (4-fluorophenyl)boric acid, and catalyst, the reaction reached an end point at which the starting material/product-ratio of 1:1 had not changed. After termination of the reaction, appropriate workup, and purification via preparative HPLC, 20 mg (0.048 mmol, 9.4%) pure N-[3-(4-fluorophenyl)pyridin-2-yl]-N′-(2-methoxybenzyl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:18])=[C:11]2[C:16]=1C(O)[CH2:14][CH2:13][CH2:12]2.C(=O)([O-])[O-].[K+].[K+]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:18][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:2](=[O:3])[O:4][CH:5]3[CH2:14][CH2:13][CH2:12][C:11]=1[C:16]=23
Reactant: COC(=O)Cl
Reactant: Nc1ccc(Br)c2c1C(O)CCC2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1Nc2ccc(Br)c3c2C(CCC3)O1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To prepare this compound, DMAP (6 mg, 0.043 mmol) and methyl chloroformate (27 mg, 0.29 mmol) were added to a solution of 8-amino-5-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (70 mg, 0.29 mol) in 1.5 mL pyridine at −10° C. The reaction was stirred for 0.5 hour, then extracted with ethyl acetate and water. The organic layer was washed sequentially with 2% aqueous HCl solution, water, and brine an then was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1.5 ml dry DMF and then potassium carbonate (80 mg, 0.58 mmol) was added. That suspension was heated at 100° C. for 2 hours, and was extracted with EtOAc and water. The organic layer from that extraction was washed sequentially with 2% aqueous HCl, water, and brine and was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 6-bromo-7,8,9,9a-tetrahydro-3H-naptho[1,8-de][1,3]oxazine-2-one. 1H NMR (500 MHz, CDCl3) δ 8.55 (broad s, 1H), 7.41 (d, J=8.2, 1H), 6.60 (d, J=8.4, 1H), 5.3-5.4 (m, 1H), 2.90 (dd, J=17.8, 5.0, 1H), 2.55-2.65 (m, 1H), 2.40-2.50 (m, 1H), 2.15-2.25 (m, 1H), 1.70-1.90 (m, 2H).
Reaction SMILES: CS(O[CH:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][C:35]([F:38])([F:37])[F:36])[CH:28]=4)[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:46])[N:15]=2)[CH2:7]1)(=O)=O.[N-:47]=[N+:48]=[N-:49].[Na+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[N:47]([CH:6]1[CH2:7][N:8]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:33]([CH2:34][C:35]([F:37])([F:38])[F:36])[C:39](=[O:40])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:28]=4)[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:46])[N:15]=2)[C:9](=[O:13])[C:10]1([CH3:12])[CH3:11])=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(OS(C)(=O)=O)C(C)(C)C2=O)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(N=[N+]=[N-])C(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.2 %

Procedure:
1-(4-(((2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazol-4-yl)carbonyl)amino)-1-methyl-1H-pyrazol-3-yl)-4,4-dimethyl-5-oxopyrrolidin-3-yl methanesulfonate (15 mg) was dissolved in DMF (0.50 mL), sodium azide (22 mg) and 18-crown-6 (5.9 mg) were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.0 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[C:23]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:31]3[CH2:32][CH2:33][N:34]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:35][CH2:36]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:20][CH2:21]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: O=C(c1ccc(N2CCCS2(=O)=O)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 66.9 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (297 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Example 109, the title compound (347 mg) was obtained.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=2)=[O:40])=[CH:35][CH:34]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)([C:41]3[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1cncc1C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(F)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (75.8 mg, 0.177 mmol, Intermediate 10) in dry THF (3 mL) in a dry ice-acetone bath. After 1 minute, a solution of (4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (37.8 mg, 0.185 mmol, Intermediate 89: step b) in dry THF (0.6 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-50% EtOAc-Hexanes) to provide the title compound as a clear foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=2.1 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.57-7.50 (m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 2H), 7.25 (s, 1H), 7.04-6.96 (m, 2H), 6.45-6.40 (m, 1H), 6.30 (s, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.34 (s, 3H); MS m/e 554.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[O:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(N)o1

Procedure:
A mixture of 53.3 g. of ethyl 5-nitro-2-furancarboxylate, 5 g. of 10% palladium on carbon, and 250 ml. of absolute ethanol is shaken in an atmosphere of hydrogen until no more hydrogen is taken up. The catalyst is filtered and the filtrate evaporated. The thick oily residue is dissolved in a small amount of methylene chloride and the solution is filtered through Magnesol. The solvent is evaporated to yield the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[F:11][CH:12]([F:27])[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1S(C)(=O)=O.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[N:14]([CH2:13][CH:12]([F:11])[F:27])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1nc2cccnc2n1CC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Cn1c(Oc2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirred solution of 4-bromophenol (238 mg) in DMF (4 mL) was added NaH (60% in oil, 55.1 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-(2,2-difluoroethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (360 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (387 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24](OC)=[O:25])[CH:21]=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=2)=[O:16])[CH:7]=[C:8]([C:10](OC)=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34]>>[N+:28]([C:20]1[CH:19]=[C:18]([NH:17][C:15]([NH:14][C:6]2[CH:7]=[C:8]([C:10]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])=[O:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:16])[CH:23]=[C:22]([C:24]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])=[O:25])[CH:21]=1)([O-:30])=[O:29]
Reactant: NC(CO)CO
Reactant: COC(=O)c1cc(NC(=O)Nc2cc(C(=O)OC)cc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Product: O=C(Nc1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1)Nc1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1
Yield: 95 %

Procedure:
The reaction was performed analogous to the synthesis described above for Example 10c starting from N,N'-bis(3-nitro-5-methoxycarbonylphenyl)urea (12.0 g, 28.7 mmol) and serinol (6.83 g, 75 mmol). The crude reaction product was purified by trituration with acetonitrile (2×50 ml), with water (200 ml) and with acetonitrile (3×50 ml) to give 95% pure product. Yield: 12.0 g (78%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH:37][CH3:38]>>[C:1]([O:5][C:6]([C:8]1[C:9]([N:37]([CH3:38])[CH3:36])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N(C)C)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 79 step A from 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 78 step C, 250 mg, 0.47 mmol) and dimethylamine (2M solution in THF, 2 ml, 2.36 mmol). Pale yellow solid (130 mg, 65%). LC-MS (ESI): 425 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH3:16]I>CO.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CI
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1

Procedure:
A mixture of 1 g (4 mmol) 2-Chloro-5-sulfino-benzoic acid in 20 ml methanol and 20 ml water was treated with 10N NaOH to pH=9 before adding 1.7 g (12 mmol) methyliodide. The mixture was heated for 48 h to 80° C. with occasional addition of NaOH to maintain pH=9. After removal of all volatiles HCl conc. was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was taken up in methanol and subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 323 mg (34%) of the title compound. MS (m/e): 233.0 (M−H, 100%)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#N)=[CH:18][CH:17]=1)([F:14])[F:13].[O:24]1CCOCC1.Cl>C(OCC)C.O>[F:11][C:12]([F:14])([F:13])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:24])=[CH:18][CH:17]=1
Reactant: C1COCCO1
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 3 h

Procedure:
Diisobutylaluminium hydride (11.8 ml. 1M solution in toluene) was added to a stirred solution of 4-cyanophenyl trifluoromethyl ether (2.0 g., Fairfield) in dry diethyl ether (100 ml.). The mixture was refluxed with stirring for 3 hours. The mixture was cooled and dioxane (5 ml.) containing water 1.0 ml.) was added. Dilute hydrochloric acid was added (60 ml. of 10% solution). The mixture was stirred for 30 minutes and extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography on silica, eluting with 9:1 hexane:diethyl ether. 4-Trifluoromethoxybenzaldehyde was obtained as a colourless liquid (1.65 g.).