Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>>[ClH:1].[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]2[CH2:19][OH:18])[N:7]=1
Reactant: OCC1CCCCN1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Product: Cc1nc(N2CCCCC2CO)c2nc(-c3ccccc3)cc-2[nH]1
Product: Cl
Temperature: 180 °C
Yield: 38 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1 (e)) (250 mg, 1.03 mmol) and 2-hydroxymethyl piperidine (Aldrich Chemical Company) (237 mg, 2.06 mmol). The flask was purged with N2 and the mixture was heated to 180° C. for 16 h. The reaction was allowed to cool to room temperature and the crude material was purified by silica gel chromatography with EtOAc as eluant to give 125 mg (38% yield) of an off white solid. 1H NMR (CDCl3; 400 MHz); d 1.74 (m, 6), 2.59 (s, 3), 3.1 (m, 1), 3.8 (m, 1), 4.35 (t, 1, J=10.9), 4.55 (m, 2), 6.72 (s, 1), 7.44 (m, 3), 7.65 (d, J=7.3), 9.9 (br, 1). MS m/z: 323.5 (M+1); 321.5 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].C(N(CC)CC)C.CCCCCCC.[C:40]([O:43][CH2:44][CH3:45])(=[O:42])[CH3:41].[O:46]1CCCC1>CN(C)C1C=CN=CC=1>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:1][C:41]([C:40]([O:43][CH2:44][CH3:45])=[O:42])=[O:46])=[C:3]([S:21][C:22]([F:25])([F:24])[F:23])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CCOC(C)=O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CCOC(=O)C(=O)Nc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
To a solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole (10.0 g, 23.7 mmol) in tetrahydrofuran was added triethylamine (3.36 g, 33.2 mmol) and 4-dimethylaminopyridine (0.58 g, 4.7 mmol), followed by dropwise addition of ethyl oxalyl chloride (4.21 g, 30.9 mmol) in tetrahydrofuran at 50-70° C. The mixture was heated to reflux for 8 hours. After extractive workup (heptane-ethyl acetate, water, HCl) the title product was obtained (13.9 g).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][CH:3]=1.[OH:19][S:20](O)(=[O:22])=[O:21].O=S(=O)=O.N1C=CC=CC=1>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1[S:20]([OH:22])(=[O:21])=[O:19]
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
60 parts of 1,4-diaminoanthraquinone are added to 228 parts of 25% oleum over one hour and then 20 parts of pyridine are added. The temperature of the reaction mixture is 70°-80° C. and is further raised to 120° C. The reaction mixture is stirred at this temperature for 3 hours, then cooled to 70°-80° C., and 220 parts of water are slowly added dropwise. The resultant thick suspension is filtered at room temperature and the filter cake is washed with 100 parts of 50% sulfuric acid and subsequently dispersed in water. The pH of the aqueous suspension is then adjusted to 7.5 with 35% sodium hydroxide solution, whereupon the 1,4-diaminoanthraquinone-2sulfonic acid goes into solution. The solution is then heated to 85°-90° C. and 40 parts of magnesium sulfate are added. Upon cooling the reaction solution, the 1,4-diaminoanthraquinone-2-sulfonic acid crystallises in the form of the magnesium salt, which is isolated by filtration, washed with a 5% solution of magnesium sulfate and dried, affording 72.4 parts of the magnesium salt of 1,4-diaminoanthraquinone-2-sulfonic acid, corresponding to a yield of 85%. According to chromatographic analysis, the product is homogeneous with a trace of starting material. The Rf value is 0.57, which confirms that this product is identical with that obtained in Example 1.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1F)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.[F:49][P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[O:6][C:5]([C:7]([NH:17][C@H:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:49])[CH:33]=2)=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](Cc1ccc(F)cc1F)CN1C(=O)c2ccccc2C1=O
Reactant: F[P-](F)(F)(F)(F)F
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)oc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccc(F)c(F)c2)CN2C(=O)c3ccccc3C2=O)oc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (200 mg, 0.77 mmol) [prepared according to the procedure of Preparation 6], 2-[(2S)-2-amino-3-(2,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (254 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.40 ml, 2.30 mmol) in DCM (10 ml) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (536 mg, 1.15 mmol). After stirring at ambient temperature for 20 hrs, the mixture was concentrated and purified with silica gel column eluting with gradient (0-50% ethyl acetate/hexanes) to afford the title compounds as an off-white foamy solid (304 mg, 0.54 mmol, 71% yield): LCMS (ES) m/e 560(M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[NH:49]1[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50]1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29]([N:49]1[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCNC1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)N3CC[C@H](O)C3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
A solution of (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (50 mg, 0.137 mmol) in CH2Cl2 (1 mL) at 0° C. was treated with triphosgene (25 mg, 0.084 mmol) followed by diisopropylethylamine (30 μL, 0.182 mmol). The reaction was allowed to warm to room temperature and stirred for 20 min then cooled to 0° C. and treated with an additional portion of diisopropylethylamine followed by pyrrolidin-3(S)-ol (30 μL, 0.37 mmol). The reaction mixture was allowed to warm to room temperature and stirred 16 h then quenched with MeOH, evaporated and purified by chromatography on silica gel using 5% MeOH/CH2Cl2 as eluant to afford the title compound as an oil (26 mg, 55%). LC/MS (Method B) 3.75 min, [M+1]+ 480.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)([CH3:13])[CH3:12].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)[C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Cl)ccc1O
Reactant: CC(C)c1ccc(CCl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(Cl)cc(Cc2ccc(C(C)C)cc2)c1O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
117.5 g (0.75 mol) 4-chloro-2-ethylphenol are dissolved with 42.25 g (0.25 mol) 4-isopropylbenzylchloride in 200 ml chloroform. 22.5 g water-free zinc chloride are added thereto for the alkylation reaction. Already at 30° C. a powerful reaction takes place. The entire mixture is after-stirred 5-6 h at 60° C. for completion of the alkylation. After a cooling it is subsequently washed three times each with 200 ml water, and then dried across sodium sulfate, after which the solvent chloroform is driven off.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[F:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][C:28]=1[CH3:35]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([F:26])=[C:28]([CH3:35])[CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1cc([Mg]Br)ccc1F
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)ccc1F

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 0.49 mL 1M 4-fluoro-3-methylphenylmagnesium bromide. Yield: 40 mg of a white solid. LC-MSD, m/z for C23H16BrFN2O2 [M+H]+=451.0, 453.0; HPLC retention time: 2.5 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl.[CH2:14]([NH:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[CH2:15][CH3:16].C(N(C(C)C)C(C)C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:27][O:26][C:21]1[CH:20]=[C:19]([C:18](=[O:28])[NH:17][CH2:14][CH2:15][CH3:16])[CH:24]=[CH:23][C:22]=1[NH:25][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCCNC(=O)c1ccc(N)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5 g (21.9 mmol) 2,4-dichloro-5-trifluoromethyl-pyrimidine are dissolved in 50 ml 1,4-dioxane and combined with 5.50 g (21.9 mmol) 4-amino-3-methoxybenzoic acid-propylamide hydrochloride (Journal of Pharmaceutical Sciences 1989, 78(10), 829-32). 7.50 ml (43.8 mmol) ethyldiisopropylamine are added to this reaction mixture and it is stirred for 2 days at ambient temperature. Then the reaction mixture is diluted with 250 ml of ethyl acetate and washed first of all with 300 ml aqueous 10% KHSO4 solution, then with 300 ml saturated, aqueous NaCl solution. The organic phase is dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:62]([O:64]C(C)(C)C)=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57]C(C)(C)C)=[CH:53][CH:52]=1)=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:30][CH2:31][C:32](=[O:38])[O:33]C(C)(C)C)=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.Cl>FC(F)(F)C(O)=O.C(S)C>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:62]([OH:64])=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:30][CH2:31][C:32](=[O:33])[OH:38])=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[CH3:31][C:32]([OH:38])=[O:33]
Reactant: CC(C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCS
Product: CC(=O)O
Product: CC(C)[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 1 h

Procedure:
1 g of H-Arg-Lys(Boc)-Glu(OBut)-Val-Tyr(But)-OBut.2HCl (0.966 mmole) is dissolved in a mixture of 10 ml of trifluoroacetic acid and 1 ml of ethylmercaptan. The mixture is allowed to stand for one hour at room temperature and is concentrated. The residue is dissolved again in a little methanol and the solution is concentrated once more. The residue is dissolved in water, insoluble matter is filtered off and the solution is chromatographed over a strongly basic exchanger in the acetate form. The eluate is concentrated and purified further by being chromatographed on a hydroxypropylated crosslinked dextran gel in a water/acetic acid/n-butanol mixture. Yield 491 mg (57%), [α]D =-21.8° (c=1, water). Aminoacid analysis: Glu 1.00, Val 0.97, Tyr 0.92, Lys 1.03 and Arg 0.99. Protein content: 82%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.Cl[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=3)[CH:8]=2)[O:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)nc1
Temperature: 55 °C
Reaction time: 80 h

Procedure:
A solution of 233 mg (1.09 mmol) of 2,2,4,4-tetramethyl-6-ethynylchroman (Compound 5) and 209 mg (1.09 mmol) of ethyl 6-chloronicotinate (Compound 9s) in 1 ml of triethylamine was degassed and then treated under argon with a powdered mixture of 50 mg (0.26 mmol) of cuprous iodide and 100 mg (0.14 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was heated under argon at 55 degrees C. for 80 h and then cooled to room temperature. The triethylamine was then removed under vacuum and the residue purified by lash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 1.36 (12H, s), 1.42 (3H, t, J~7.2 Hz), 1.85 (2H, s), 4.37 (2H, q, J~7.2 Hz), 6.79 (1H, d, J~4 Hz), 7.34 (1H, dd, J~8.4 Hz, 2.1 Hz), 7.56 (1H, d, J~8.7 Hz), 7.60 (1H, d, J~2.1 Hz), 8.27 (1H, dd, J~8.7 Hz, 2.4 Hz), 9.19 (1H, d, J~2.4 Hz). MS exact mass, m/e 363.1837 (calcd. for C23H25O3N, 363 1834).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 38 %

Procedure:
A solution of 3-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (240 mg, 0.47 mmol, 1.00 equiv), cyclopropanecarbaldehyde (98.7 mg, 1.41 mmol, 3.00 equiv) and piperidine (42 mg, 0.47 mmol, 1.00 equiv) in ethanol (15 mL) was stirred for 3 h at 65° C. The resulting mixture was concentrated under vacuum. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 100 mg (36%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 560(M+1) H-NMR (400MHz, CD3OD, ppm): 8.36 (s, 1H), 7.68-7.65 (t, J=7.6 Hz, 1H), 7.30-7.20 (m, 2H), 7.14-7.11 (t, 1H), 7.03-7.00 (d, J=9.2 Hz, 2H), 6.58 (d, J=10.8 Hz, 1H), 4.92-4.87(m, 1H) 3.65-3.60 (m, 1H), 3.50-3.46 (m, 1H), 2.14 (m, 1H), 1.99-1.81 (m, 4H),1.24-1.23(m, 2H), 0.93-0.77(m, 2H).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=O)[CH:3]=[CH:2]1.[C:8]([OH:12])(=O)[CH:9]=[CH2:10].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:1]([O:7][CH2:10][CH:9]1[O:12][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:13][CH3:19]
Reactant: C=CC(=O)O
Reactant: Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Product: CCCCCCCCCCCCCCCCCCOCC1CO1

Procedure:
In a 2 L-volume four-necked flask equipped with a stirrer, a cooling tube, a thermometer and a dropping funnel, 140 g of the obtained maleic anhydride-modified chlorinated propylene-based random copolymer, 60 g of the ester group-containing acrylic acid copolymer obtained in Production Example 1, 8 g of the stabilizer (stearylglycidyl ether) and 36 g of toluene were added and kneaded at 120° C. for 30 minutes. Subsequently, 8 g of 2-amino-2-methyl-1-propanol was added over 5 minutes, then it was kept for 5 minutes. After that, 970 g of hot water at 90° C. was added over 40 minutes. A reduced pressure treatment was performed to remove toluene. Then the reactant was cooled to room temperature with stirring, yielding an aqueous resin composition of the maleic anhydride-modified chlorinated propylene-based random copolymer.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:9]([NH:11][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:24]=2[F:23])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(N)cn1S(C)(=O)=O
Reactant: O=C(Cl)c1cccc(F)c1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(NC(=O)c2cccc(F)c2F)cn1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a solution of 4-amino-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid ethyl ester (1 g, 4.3 mmol) and triethylamine (650 mg, 6.4 mmol) in dry CH2Cl2 (20 mL) was added 2,3-difluoro-benzoyl chloride (760 mg, 4.3 mmol). The mixture was stirred at RT for 3 h and diluted with EtOAc (150 mL). After washing with 2N HCl (80 mL) and NaHCO3 (2×80 mL), the organic layer was dried over MgSO4, filtered, and evaporated to give a yellow solid (1.3 g, 81%). This solid was dried on the vacuum pump for 14 hrs and then was used for the next step directly. MS (ES+): m/e=373.2 (M+H); LC: 3.45 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([O:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:53]4[CH2:54][CH2:55][CH:50]([O:49][CH2:47][CH3:48])[CH2:51][CH2:52]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCOC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCC(OCC)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-ethoxypiperidine (VWR) to give the title product. LC-MS (ES+) 776 [(M+H)+].
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([N+]([O-])=O)[CH:14]=1.O>CN(C)C=O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:14]=1
Reactant: CC(C)=NO
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(Cl)ccc1C#N
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
In 75 ml of dry N,N-dimethylformamide was dissolved acetone oxime (1.21 g), followed by potassium tertiary butoxide (1.85 g) and stirred under nitrogen. After 30 minutes, 4-chloro-2-nitro-benzonitrile (2.00 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of the product, m.p. 83-84° C.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Li+].O>C1COCC1>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Yield: 89.1 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (240 mg, 0.1 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (278 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMA (5 mL) was stirred at 120° C. for 16 hours. The solution was poured into water (30 mL) and acidified with 1N hydrochloric acid before being extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (as evidenced by LCMS data only m/z 435 (M+H)+) as a brownish oil (550 mg). The crude methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (434 mg, 1 mmol) was dissolved in THF (15 mL) and methanol (5 mL) then 1N aqueous Lithium hydroxide solution (2 mL) added followed by the dropwise addition of water until a clear solution obtained. The mixture was stirred was stirred for 4 hours at RT and the organics removed by evaporation. The aqueous solution was filtered, extracted with ethyl acetate (10 mL) and the aqueous layer acidified with 2N hydrochloric acid. The acidified layer was extracted with ethyl acetate (3×30 mL) and the combined organic extracts washed with water (10 mL), brine (10 mL) and concentrated in vacuo to give the desired compound as a pale oil (375 mg). 1H NMR δ (CDCl3): 1.27 (d, 3H), 2.32 (quin, 2H), 3.34 (s, 3H), 3.42-3.55 (m, 2H), 4.13-4.34 (m, 4H), 4.54 (q, 1H), 6.93 (s, 1H), 7.40 (s, 1H), 7.48 (s, 1H), 8.08 (s, 1H), 8.19 (s, 1H), m/z 421 (M+H)+