Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:37])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:38]([O:40]CC)=[O:39].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:37])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C(F)(F)F)cc5)nn4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (1.83 g, 3.07 mmol) in 40 mL of 3:1 THF/EtOH was added sodium hydroxide (12.3 ml, 12.3 mmol). The reaction was stirred for 3 hours, then concentrated. The crude material was combined with 1M HCl (50 mL) and stirred for 3 hours. The material was resolved via supercritical fluid chromatography employing a CHIRALCEL® OJ-H column (3×15 cm) eluting with 35% ethanol/carbon dioxide at 100 bar, using 3 mL injections and a flow rate of 140 mL/min. Collection of fractions containing peak 2 and removal of volatiles provided Enantiomer 2 of 6-chloro-7-(4-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.730 g, 1.29 mmol, 41.9% yield) as a white solid. MS (apci, positive) m/z=569.9.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1>CC(=O)OCC.[Pd]>[NH2:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=3)=[CH:31][N:32]=2)=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(C(C)(C)C)cc3)cn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(-c2ncc(-c3ccc(C(C)(C)C)cc3)cn2)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-10 (757 mg, 1.34 mmol) in EA (100 ml) was added Pd/C (142 mg, 0.13 mmol) and the suspension degassed with H2. The mixture was stirred vigorously under an atmosphere of H2 overnight then filtered through celite and the filtrate was concentrated to give 532 mg (88%) of (S)-tert-butyl 2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-11. LCMS-ESI (m/z) calculated for C27H33N3O2: 431.3. found: 432.0 [M+H]+, tR=2.01 min (Method 4).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[OH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[C:7]1=[O:14].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:11]([N:8]1[CH2:9][CH2:10][C@@H:6]([O:5][CH2:1][O:2][CH3:3])[C:7]1=[O:14])[C:12]#[CH:13]
Reactant: COCCl
Reactant: C#CCN1CC[C@@H](O)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN1CC[C@@H](OCOC)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g of chloromethyl methyl ether in 15 ml of methylene chloride is added dropwise to a solution of 1.5 g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, prepared by the procedure of Example 1, U.S. Pat. No. 5,089,518, and 1.5 g of ethyldiisopropylamine in 15 ml of methylene chloride which is stirred in an ice bath. The reaction is allowed to warm to room temperature and stirred overnight. The solution was washed with water, aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The methylene chloride solution is concentrated at reduced pressure and purified by column chromatography (silica gel: mehylene chloride) to give the product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C@@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:27]([NH:29][O:30]C4CCCCO4)=[O:28])[C:20](=[O:42])[CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>CC(O)C>[OH:30][NH:29][C:27](=[O:28])[C@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:25][CH2:24][N:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:7]3[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[CH:17][CH:16]=2)=[CH:19][C:20]1=[O:42]
Reactant: COc1ccc(COc2ccc(-c3ccn(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)c(=O)c3)cc2)cn1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(COc2ccc(-c3ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c3)cc2)cn1

Procedure:
HCl (1.0 N in water, 2.09 mL) was added to a solution of the (2R)-4-[4-{4-[(6-methoxypyridin-3-yl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (245 mg, 0.418 mmol) in IPA (5.0 mL) for 1 hour. The reaction mixture was concentrated and the residue was triturated with IPA to afford a white suspension at 50° C. for 30 minutes. A white solid was collected by filtration. Yield 215 mg/95% LCMS MS ES-500.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 3H) 2.07-2.23 (m, 1H) 2.33-2.43 (m, 1H) 3.08 (s, 3H) 3.64-3.79 (m, 1H) 3.83 (s, 3H) 4.00-4.12 (m, 1H) 5.09 (s, 3H) 6.57-6.67 (m, 2H) 6.80-6.88 (m, 1H) 7.05-7.12 (m, 2H) 7.64-7.73 (m, 3H) 7.78 (s, 1H) 8.26 (s, 1H).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])(C)(C)C.[C:18]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CO.CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[NH:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCNC(=O)CCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)CCCNC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrochloric acid (12%, 64 ml) was added to a cold solution of Boc-derivative 3 (21.1 g, 91.7 mmol) in MeOH (190 ml) and stirred overnight at room temperature. The next day additional acid (30 ml) was added and stirring was continued for another 10 h. The reaction mixture was filtered, washed with CHCl3, concentrated and dried in vacuo overnight. The product was suspended in DMF (300 ml) with DIEA (42 ml), cooled to 0° C. and a solution of Bt-derivative 2 (29 g, 90.5 mmol) in DMF (100 ml) was added into the reaction mixture. The cooling bath was removed and the stirring was continued overnight. The solvent and DIEA were removed in vacuo at 45° C., the residue was suspended in CHCl3/H2O mixture, washed with H2O, aq. KHSO4 (20%), H2O, aq. NaHCO3 (2 times with each), dried (Na2SO4), concentrated in vacuo, and triturated with petr. ether. Yield 22.32 g (78%). mp: 134-1350. 1H (CDCl3): 1.15 (t, J=7.27, 3H), 1.44 (s, 9H), 1.65-1.95 (m, 4H), 2.20-2.26 (m, 4H), 3.19 (q, J=6.15, 2H), 3.23-3.35 (m, 4H), 4.82 (bs, 1H), 6.40 (bs, 1H), 6.68 (bs, 1H). 13C (CDCl3): 14.77, 24.92, 25.66, 26.43, 28.38, 33.59, 33.84, 33.92, 34.35, 38.83, 39.66, 79.35, 156.56, 172.65, 173.12. ESI-MS: 338.2 (MNa+), 316.0 (MH+), 216.0 (MH+-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][C:26]1[N:31]=[C:30](Cl)[C:29]([C:33]#[N:34])=[C:28]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=2)[N:27]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][C:26]1[N:31]=[C:30]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:29]([C:33]#[N:34])=[C:28]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=2)[N:27]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc(Cl)c2C#N)c1
Reactant: Oc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc(Oc3ccccc3Cl)c2C#N)c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
o-Chlorophenol and 60% sodium hydride were added to a mixture of 2-[cis-2-(tert-butoxycarbonylamino)cyclohexylamino]-4-chloro-6-(3-methylanilino)pyrimidine-5-carbonitrile and DMF, followed by stirring at room temperature for 30 minutes and at 70° C. for 5 hours. Thereafter, purification in the usual way afforded 2-[cis-2-(tert-butoxycarbonylamino)cyclohexylamino]-4-(2-chlorophenoxy)-6-(3-methylanilino)pyrimidine-5-carbonitrile (colorless solid).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:12](#[N:15])[CH:13]=[CH2:14].S(=O)(=O)(O)O>C(OCC)(=O)C>[C:1]1([S:7][CH2:8][CH2:9][O:10][CH2:14][CH2:13][C:12]#[N:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCSc1ccccc1
Reactant: C=CC#N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCOC(C)=O
Product: N#CCCOCCSc1ccccc1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
a well defined print in a full yellow shade is obtained with no staining on adjacent white carpet. The wash off liquor contains a negligible quantity of colour. The 3-[2'-(phenylthio)ethoxy]propionitrile used as printing assistant in the above Example 4 is prepared as follows: 15.4 g 2-(phenylthio)ethanol and 0.3 g of a concentrated aqueous mixture of sodium and potassium hydroxides are stirred at room temperature and treated with 6.0 g acrylonitrile over a period of 2 hours. The temperature is not allowed to rise above 42°C. After the addition, stirring is continued for a further 2 hours. The alkaline catalyst is then neutralised with dilute sulphuric acid, the organic product is dissolved in ethyl acetate, washed with water, separated and dried over magnesium sulphate. The ethyl acetate is distilled leaving 18.3 g of 3-[2'-(phenylthio)-ethoxy]propionitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][N:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][N:34]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cn4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 2-bromo-5-methanesulfonyl-pyridine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)([O:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(CCO)cc1
Solvent: c1ccncc1
Product: Cc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.8 ml of 2-p-tolylethanol are introduced into 40 ml of pyridine with ice-bath cooling, treated with 4.96 g of p-toluenesulphonyl chloride, and stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture is then slowly stirred into about 150 g of ice/water. The precipitated product is filtered off with suction, washed a number of times with water, dissolved in methylene chloride, dried over magnesium sulphate and concentrated in vacuo. 5.8 g of 2-p-tolylethyl tosylate are obtained, which is employed in the next stage without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[C:4](F)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:19][NH2:20]>CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:19][N:20]=[C:11]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12
Reactant: COc1ncc(Br)c(C(=O)C2CCCC2)c1F
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ncc(Br)c2c(C3CCCC3)n[nH]c12
Reaction time: 3 h

Procedure:
To a solution of (5-bromo-3-fluoro-2-methoxypyridin-4-yl)(cyclopentyl)methanone (440 mg) in methanol (10 mL) was added hydrazine monohydrate (2.06 mL) at room temperature, the mixture was stirred for 3 hr, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (100 mg).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1(/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-phenyl-acrylic acid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([NH2:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[C:8]([Br:27])[CH:7]=1.[F:30][C:31]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:32]=1[CH:33]=[CH:34][C:35](O)=[O:36]>>[Br:27][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:28][C:35](=[O:36])[CH:34]=[CH:33][C:32]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:31]=2[F:30])[C:3]([OH:2])=[O:29])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(Br)c1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](NC(=O)C=Cc2ccc(F)cc2F)C(=O)O)cc1Br
Yield: 31 %

Procedure:
Following the procedures described in Example 1, Intermediate 3B was used in place of Intermediate 3A, and 2,4-difluorocinnamic acid was used in place of cinnamic acid to give (2S)-3-{3-bromo-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-phenyl}-2-(3-(2,4-difluorophenyl)-acryloylamino)-propanoic acid as a white solid with the yield of 31% and mp of 221-223° C.
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.[CH2:38]([O:40][C:41]([CH3:45])([CH3:44])[CH:42]=O)[CH3:39].N1CCCCC1>CCO>[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:42][C:41]([O:40][CH2:38][CH3:39])([CH3:45])[CH3:44])[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: CCOC(C)(C)C=O
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 12.4 %

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 (202.8 mg, 0.40 mmol, 1.0 equiv), 2-ethoxy-2-methylpropanal (232 mg, 2.00 mmol, 5.0 equiv), piperidine (68 mg, 0.80 mmol, 2.0 equiv) in EtOH (20 mL) was stirred at room temperature overnight. The volatile phase was removed off under reduced pressure. 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 in 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 30 mg (10.43%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 606 (M-TFA+1)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]([CH3:40])[S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:43][N:42]=[N:41][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]([CH3:40])[S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:32])=[O:33])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2c(C)cc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[C:2]1([C:1]2[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:19][N:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: c1ccc(C2=NNC(c3ccccc3)C2)cc1

Procedure:
Benzalacetophenone (12.5 parts) is reacted with hydrazine hydrate (3.1 parts by volume) in methanol to form 3,5-diphenyl-2-pyrazoline. Panasol AN-2 (30 ml), nitrobenzene (7.4 parts) and 5% palladium on carbon catalyst (2 parts) are then added and the mixture heated. Following the distillation of methanol and water from the reaction mixture, the temperature is raised to 200°C. and held at that temperature for 24 hours. The mixture is then cooled to 50°C., filtered, and the catalyst bearing cake of 3,5-diphenylpyrazole is 79.5%, m.p. 194°C. to 199°C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([Br:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([Br:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)nc2cc(Br)ccc12
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2ccc(Br)cc2n1
Yield: 89.5 %

Procedure:
A mixture of 3.00 g (12.00 mM) of 2-chloro-4-methyl-7-bromoquinoline and 0.63 g (12.00 mM) of sodium methoxide was heated to reflux in 30 mL of dry methanol for 48 h. The methanol was then removed in vacuo, and the resultant concentrate was taken up in methylene chloride. This methylene chloride solution was washed repeatedly with saturated sodium chloride. After drying (MgSO4), solvent removal, and recrystallisation from toluene, 2.63 g (87%) of the product was obtained as white crystals: mp 58°-60° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH2:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15]>C1COCC1>[CH2:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)[CH3:15]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCN1CCN(c2ncc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Temperature: 60 °C
Yield: 120.9 %

Procedure:
3 g (14.7 mmol) of 2-chloro-3,5-dinitropyridine, 20 ml of THF and 30 mmol of 4-ethylpiperazine were placed in a round-bottomed flask. The mixture was maintained at 60° C. for two hours with stirring and was then poured into a mixture of ice-water with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 5 g of yellow powder were obtained.
Reaction SMILES: C([O:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[S:22][C:13]2[C:14]([CH3:21])([CH3:20])[O:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:12]=2[C:11]=1[C:23]([NH2:25])=[O:24])=[O:8])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCOCC1>[OH:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[S:22][C:13]2[C:14]([CH3:21])([CH3:20])[O:15][C:16]([CH3:18])([CH3:19])[CH2:17][C:12]=2[C:11]=1[C:23]([NH2:25])=[O:24])=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1sc2c(c1C(N)=O)CC(C)(C)OC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)Cc2c(sc(NC(=O)c3ccccc3O)c2C(N)=O)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-acetoxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide (200 mg, 0.48 mmol) in 4 mL of MeOH/dioxane=1:1, cooled to 0° C., is added potassium carbonate (66 mg, 0.52 mmol). The reaction mixture is stirred at room temperature for 90 min, filtered off and filtrate is then acidified with 1M HCl. A precipitate is formed which is separated by filtration to afford the desired compound which is used as such.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:17][C:14]1[CH:13]=[C:12]2[NH:11][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:10])[N:16]2[N:15]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Cc1cc(N)[nH]n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc2[nH]c3ncccc3c(=O)n2n1
Reaction time: 2 h

Procedure:
157 g. of 2-chloropyridine-3-carboxylic acid and 194 g. of 5-amino-3-methylpyrazole are heated together in 500 ml. of diphenyl ether for 10 minutes at 215°. After this time, the mixture is allowed to stand at room temperature for 2 hours and is then filtered. The crystalline 2-methylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin- 9(4H)-one is washed with methanol and recrystallized from dimethylformamide, yield: 120 g. (64%); m.p. >300°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)=[C:6]([Cl:18])[C:3]=1[C:4]#[N:5].Cl.Cl[C:21]([NH2:23])=[NH:22]>COCCOCCOC>[NH2:23][C:21]1[N:22]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([C:10]3[CH:11]=[C:12]([Cl:17])[CH:13]=[C:14]([Cl:16])[CH:15]=3)[C:6]=2[Cl:18])[N:1]=1
Reactant: N#Cc1c(N)ccc(-c2cc(Cl)cc(Cl)c2)c1Cl
Reactant: N=C(N)Cl
Agent: Cl
Solvent: COCCOCCOC
Product: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)cc(Cl)c3)ccc2n1
Yield: 29.4 %

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, using 1.5 grams (0.005 mole) of 2-amino-6-chloro-5-(3,5-dichlorophenyl)benzonitrile and 0.7 gram (0.006 mole) of chloroformamidine hydrochloride in 10 mL of 2-methoxyethyl ether. The solid was recrystallized from methanol, yielding 0.5 gram of 2,4-diamino-5-chloro-6-(3,5-dichlorophenyl)quinazoline. The NMR spectrum was consistent with the proposed structure; however, methanol was present in the sample.