Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][CH:4]=O.[NH2:12][C:13]1[C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][NH:15][N:14]=1>C(O)(=O)C>[C:20]1([C:18]([C:17]2[CH:16]=[N:15][N:14]3[C:2]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)=[CH:3][CH:4]=[N:12][C:13]=23)=[O:19])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=CC=C(Cl)c1cccnc1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.02 mole of 3-chloro-3-(3-pyridinyl)-2-propenal and 0.02 mole of (3-amino-1H-pyrazol-4-yl)phenyl-methanone in 25 ml of glacial acetic acid was refluxed for 5 hours. The solvent was removed and the product isolated as described in Example 1, giving the desired product as crystals, mp 202°-203° C.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.C(C(=O)C(=NO)C)C.[F:29][C:30]([F:40])([F:39])C1C=CC=CC=1C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:30]([F:40])([F:39])[F:29])[O:6][C:7]=1[CH2:8][CH3:13]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2ccccc2C(F)(F)F)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-ethyl-1,2-propanedione-2-oxime and 2-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-ethyl-2-(2-trifluoromethylphenyl)oxazole.
Reaction SMILES: C([O:3][C:4](=[O:34])/[C:5](/[O:31][CH2:32][CH3:33])=[CH:6]/[C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)C.[Li+].[OH-].Cl>O1CCOCC1.O>[CH2:32]([O:31]/[C:5](=[CH:6]\[C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)/[C:4]([OH:34])=[O:3])[CH3:33]
Reactant: CCOC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
2Z-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-acrylic acid ethyl ester (example 91 c]) (150 mg, 0.325 mmol ) was dissolved in 1.7 ml of dioxane, 0.9 ml of water were added and LiOH (0.812 ml of a 1N solution in water, 0.813 mmol) was then added slowly at room temperature. The resulting mixture was stirred overnight at room temperature. It was then poured onto ice, neutralized to pH 4 with HCl (1N) and extracted 3 times with AcOEt. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give 140 mg (99.4%) of 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-acrylic acid as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][CH:14]([CH3:15])[C:13]([C:9]1[C:10]([CH3:12])=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:16]
Reactant: CCC(=O)c1cc(C(=O)OC)c(C)cc1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)C(C)Br)c(C)cc1C
Temperature: 20 °C
Reaction time: 2 h
Yield: 122.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 2,4-dimethyl-5-propionylbenzoate (compound 1.5, 600 mg, 2.72 mmol) in chloroform (20 mL). Bromine (154 μL, 3.00 mmol) was added and the resulting solution was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure to yield the title compound as a yellow oil (1.0 g, crude), which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23](C)[C:24](=O)C(F)(F)F)=[CH:18][CH:17]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])([OH:3])=[O:2].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][NH:23][CH3:24])=[CH:20][CH:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])([OH:3])=[O:2]
Reactant: CN(Cc1ccc(-c2nc3cc(C(=O)NCCC(=O)O)ccc3n2C)cc1)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CNCc1ccc(-c2nc3cc(C(=O)NCCC(=O)O)ccc3n2C)cc1

Procedure:
Prepared from 5-[(2-carboxy-ethyl)-aminocarbonyl]-1-methyl-2-[4-(N-trifluoroacetyl-methylaminomethyl)-phenyl]-benzimidazole by treating with 2N sodium hydroxide solution.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[N:23]=[C:22]4[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[N:23]=[C:22]4[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3cccnc3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(c3)c(-c3cccnc3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a vial was dissolved (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(pyridin-3-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate (69 mg, 0.11 mmol) in THF (2 mL) and EtOH (1 mL). 1M NaOH (1 mL) was added, and the mixture was heated to 50° C. for 15 hours. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product as a light yellow powder. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.1 (M+H+); Found: 597.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 9.32 (s, 1H), 8.89 (d, J=8.1 Hz, 1H), 8.72 (d, J=4.5 Hz, 1H), 8.66 (s, 1H), 8.09 (dd, J=8.9, 1.4 Hz, 1H), 7.95 (dd, J=7.9, 5.5 Hz, 1H), 7.79 (s, 1H), 7.76-7.67 (m, 2H), 7.63-7.52 (m, 3H), 5.26 (s, 1H), 4.17 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH2:6][CH3:7])[C:4]#[N:5])[CH3:2].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[CH2:1]([C:3]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)([CH2:6][CH3:7])[CH:4]([NH2:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: [Li]c1ccccc1
Reactant: CCC(C#N)(CC)N1CCCC1
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(C(N)c1ccccc1)N1CCCC1
Yield: 88 %

Procedure:
The title compound (11.5 g, 88%) was prepared from 2-ethyl-2-(1-pyrrolidinyl)butanenitrile D17 (8.8 g, 0.053 mol) and phenyllithium in dibutylether (59 ml of a 1.8M solution; 0.106 mol) in THF (350 ml), followed by reaction with sodium borohydride (3.9 g, 0.103 mol) in methanol (300 ml) in a similar manner to that described in D5. 1H NMR (CDCl3) δ: 0.75 (3H, t), 0.95 (3H, t, J=7.6 Hz), 1.50-1.90 (10H, m), 2.70-2.95 (4H, m), 4.01 (1H, s), 7.19-7.41 (5H, m).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:12])/[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.[C:13]1([C:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28](F)=O)[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:13]1([C:19]2[C:23]([C:24]([F:26])([F:27])[F:25])=[C:22]([C:28]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=4)[N:12]=3)[O:21][N:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc(/C(N)=N/O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=Cc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 62 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
To a mixture of (Z)—N′-hydroxy-4-vinylbenzimidamide (1.439 g, 8.87 mmol) and 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.300 g, 8.87 mmol) in acetonitrile was added DIEA (1.860 mL, 10.65 mmol). The reaction mixture was heated to 62° C. After 3 hours, the reaction mixture was cooled and a white solid precipitate formed. The solid was filtered and washed with ethyl acetate, then dried to give about 2.1 g of 5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3-(4-vinylphenyl)-1,2,4-oxadiazole. MS (m+1)=384. HPLC Peak RT=1.24 minutes (Analytical Method B).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:27]5[C:32]([O:33][C@H:34]([CH2:36]C=C)[CH3:35])=[CH:31][CH:30]=[CH:29][C:28]=5[Cl:39])[C:23]([CH3:26])=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44][CH3:45])=[O:43])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[Cl:39][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[C:22]1[CH:21]=[C:20]([C:18]3[CH:19]=[C:15]4[N:14]=[C:13]([CH3:40])[C:12]([C@H:41]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])[C:42]([O:44][CH3:45])=[O:43])=[C:11]([N:8]5[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH:2]=[CH:3][CH2:35][C@H:34]([CH3:36])[O:33]2)[CH2:10][CH2:9]5)[N:16]4[N:17]=3)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4ccc(C)c(-c5c(Cl)cccc5O[C@@H](C)CC=C)c4)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cccc(Cl)c1-c1cc-3ccc1C
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a solution of (2S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-chloro-6-methyl-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.140 mmol, 1.0 equiv) in DCE (7 mL) was added Hoveyda-Grubbs Catalyst 2nd Generation (8.76 mg, 0.014 mmol, 0.1 equiv) and stirred for 3 h at 95° C. The solvent was evaporated to give a grey solid which was used in the next step without further purification. LCMS (M+1)=687.3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23](OC)=[O:24])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]2[C:5]([CH:6]=[C:22]([C:16]3[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:14]([O:13][CH3:12])[CH:15]=3)[C:23](=[O:24])[N:10]2[CH3:11])=[CH:4][N:3]=1
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1
Reactant: CNc1cc(Cl)ncc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)cc3n(C)c2=O)c1
Temperature: 105 °C
Yield: 80.8 %

Procedure:
A mixture of 6-chloro-4-(methylamino)nicotinaldehyde (3.7 g, 21.7 mmol), methyl 2-(3,5-dimethoxyphenyl)acetate (4.5 g, 21.7 mmol) and potassium carbonate (9.0 g, 65.1 mmol) in N,N-dimethylformamide (30 mL) was heated at 105° C. for 5 h. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (200 mL), and filtered. The filtration cake was washed by petroleum ether (50 mL) and ethyl acetate (50 mL) to afford the title compound (5.8 g, 77%) as a yellow solid. MS (ES+) C18H19ClN2O3 requires: 346, 348. found: 347, 349 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].CC(=CC)C.Cl([O-])=[O:44].[Na+].[H-].P(O)(O)(O)=O.[Na+]>O>[Cl:17][C:14]1[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:25]([OH:44])=[O:26])=[C:12]([F:29])[C:11]([CH2:10][NH:9][C:7]([C:6]2[N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:4]=[N:3][C:2]=2[Cl:1])=[O:8])=[CH:16][CH:15]=1
Reactant: [O-][Cl+][O-]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C=O)c2)c1F
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [H-]
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(=O)O)c2)c1F
Reaction time: 4 h
Yield: 63.2 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (200 mg, 0.355 mmol) in 2-methyl-2-butene (4.44 ml, 4.44 mmol) was added a solution of sodium chlorite (401 mg, 3.55 mmol) and sodium dihydrogenphosphate monohydride (302 mg, 2.130 mmol) in water (2 mL). The mixture was stirred for 4 hours and the solvent was removed under vacuum. The residue was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC (MeCN/water 0.1% formic acid) to give 130 mg (63%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (t, 1H), 7.88-8.14 (m, 2H), 7.81 (s, 1H), 7.31-7.61 (m, 3H), 5.49 (s, 2H), 4.35-4.59 (m, 2 H), 3.31 (s, 2H), 0.57-0.85 (m, 2H), −0.09 (s, 9H). LC-MS (ES+) m/z 578.25, [M+H].
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:14][C:15]1([CH2:20][NH2:21])[CH2:19][CH2:18][O:17][CH2:16]1>>[CH3:14][C:15]1([CH2:20][NH:21][C:2]2[C:7]3[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CSc1ncc2ccnc(Cl)c2n1
Reactant: CC1(CN)CCOC1
Product: CSc1ncc2ccnc(NCC3(C)CCOC3)c2n1

Procedure:
The title compound was prepared according to the method described for Preparation 175 using of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33) and (3-methyltetrahydrofuran-3-yl)methanamine at 130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[CH:14]=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[NH2:30][C@@H:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][C:33]([OH:35])=[O:34].C([O-])([O-])=O.[Na+].[Na+].Cl>C1COCC1.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:30][C@@H:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][C:33]([OH:35])=[O:34])[CH:14]=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[C@H](N)CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(S(C)=O)n3)c3cc(F)cnc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(N[C@H](CC(=O)O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 125 °C
Yield: 31 %

Procedure:
A mixture of 5-fluoro-3-(4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 127a, (0.052 g, 0.121 mmol) and (3R)-3-amino-4,4-dimethyl-pentanoic acid, 2a, (0.035 g, 0.242 mmol) along with Na2CO3 (0.051 g, 0.483 mmol) in a mixture of THF (0.780 mL) and acetonitrile (0.260 mL) was heated to 125° C. for 30 minutes under microwave irradiation. Then, the temperature was raised to 150° C. for a further 2.5 hours. The mixture was neutralized with aqueous 2N HCl and extracted with several portions of EtOAc. The organic solvents were evaporated in vacuo. Purification by flash chromatography (SiO2, 0-100% hexanes-EtOAc (with 10% MeOH)) provided 19 mg of the desired material (31% yield), which was used in the next step without further purification: LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, RT=2.70 minutes (M+H) 512.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@H:10]3[C:16](=O)[N:15](COCC[Si](C)(C)C)[C:14]4[CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]5[C:38]([O:68][CH3:69])=[CH:39][C:40]6[C:46](=[O:47])[N:45]7[CH:48]=[C:49]([C:51]8[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=8)[CH2:50][C@H:44]7[C:43](=O)[N:42](COCC[Si](C)(C)C)[C:41]=6[CH:67]=5)[C:28]([O:30][CH3:31])=[CH:29][C:13]=4[C:12](=[O:70])[N:11]3[CH:71]=2)=[CH:4][CH:3]=1.C([BH-](CC)CC)C.[Li+]>O1CCCC1.ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@H:10]3[CH:16]=[N:15][C:14]4[CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]5[C:38]([O:68][CH3:69])=[CH:39][C:40]6[C:46](=[O:47])[N:45]7[CH:48]=[C:49]([C:51]8[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=8)[CH2:50][C@H:44]7[CH:43]=[N:42][C:41]=6[CH:67]=5)[C:28]([O:30][CH3:31])=[CH:29][C:13]=4[C:12](=[O:70])[N:11]3[CH:71]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(O)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(O)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
A flame-dried flask was charged with SEM dilactam 13 (109 mg, 109 μmol, 1 eq) dissolved in anhydrous tetrahydrofuran (2.2 mL), and cooled to −78° C. Lithium triethylborohydride (0.33 mL of a 1 M solution in THF, 330 μmol, 3 eq) was added dropwise and the reaction was stirred under nitrogen for 2.5 hours, at which time LC revealed incomplete conversion to product. An additional 0.66 mL of reductant was added and the reaction was stirred for one more hour. The reaction was quenched through the addition of water (1 mL) and allowed to warm to room temperature, then diluted brine (25 mL) and extracted three times with dichloromethane (25 mL). The combined organics were washed with brine (25 mL), dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in a mixture of dichloromethane (2.8 mL), ethanol (7.4 mL), and water (1.0 mL), and silica gel (2.7 g) was added. The resulting slurry was stirred at room temperature for 4 days. TLC analysis revealed conversion to imine dimer 14, at which time the slurry was filtered over a sintered glass funnel and the silica gel cake was washed with 10% methanol in chloroform until no further PBD absorbance was observed in the filtrate. Concentration of the filtrate provided crude imine dimer 14. The material was dissolved in minimal dichloromethane and purified by radial chromatography on a 1 mm chromatotron plate eluted with CH2Cl2/MeOH mixtures (100:0 to 80:20) to provide 14 (31 mg, 40%). LC-MS: tR 8.48 min, m/z (ES+) found 712.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[N:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][CH:2]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(N=C(C)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(C)c2ccccc2)cc1

Procedure:
N-(α-methyl benzylidene)-p-carbethoxyaniline (XI) prepared by the procedure described in example XXIIA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent to give N-(α-methyl benzyl)-p-carbethoxy aniline (XII). XII had a m.p. of 88° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.CC(O)=[O:29].O.C([O-])(O)=O.[Na+]>Br.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:25]([NH2:26])=[O:29])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: CC(=O)O
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccc(F)cc2)ccc1=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccc(F)cc2)ccc1=O

Procedure:
A solution of 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile (30 mg) in 28% hydrogen bromide solution of AcOH (2 ml) was stirred at 25° C. for 3 hours. Water, aq. NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of CHCl3 and MeOH. The fractions were concentrated in vacuo to obtain 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide (30 g) as white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].CO.C([O-])(=O)C.[NH4+:15].[Cl-].[NH4+]>O1CCCC1.CN(C=O)C.C(O)(C)C.C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)(=[NH:15])[NH2:2]
Reactant: [NH4+]
Reactant: N#Cc1ccccn1
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: N=C(N)c1ccccn1

Procedure:
The novel 4-amino-2-(2-pyridyl)pyrimidines are prepared by methods known per se (J. Org. Chem.; 1967, 32, 1591). For that purpose, 2-cyanopyridine is reacted, in a suitable solvent, for example methanol, ethanol, isopropanol, DMF, tetrahydrofuran etc., with ammonium acetate or ammonium chloride at a temperature of from −10° C. to 100° C. over a period of from 1 hour to 24 hours to form the corresponding 2-amidinopyridine. The 2-amidinopyridine is then condensed with an appropriate β-keto ester using an auxiliary base, for example sodium carbonate, potassium hydroxide, sodium ethanolate, sodium methanolate, potassium tert-butanolate etc., in a suitable solvent, for example methanol, ethanol, butanol, tert-butanol, THF, DMF, acetonitrile, toluene, xylene etc., over a period of from 1 to 24 hours at a temperature of from 40 to 120° C. The 4-hydroxy-2-(2-pyridyl)pyrimidine thereby obtained is then converted into the corresponding 4-chloro-2-(2-pyridyl)pyrimidine by conventional methods using phosphorus oxychloride. The substituted 4-amino-2-(2-pyridyl)pyrimidines are obtained by reacting the 4-chloro-2-(2-pyridyl)pyrimidine with primary or secondary amines in a suitable solvent, for example DMF, dioxane, toluene, xylene, ethanol, butanol, and an auxiliary base, for example triethylamine, DIEA, sodium carbonate, potassium hydroxide etc., or using an excess of amine at from 40 to 130° C. over a period of from 1 to 24 hours. Preparation of the compounds of formula (2), except for the reaction with polymer-bound diamines, is analogous to that of compound (1). The polymer-bound diamines are obtained by reacting an excess of from 2 to 10 equivalents of diamine in, for example, DMF, dichloromethane, THF or dioxane with trityl chloride polystyrene resin at a temperature of from 10 to 50° C. over a period of from 0.5 to 24 hours. From 2 to 10 equivalents of appropriately substituted 4-chloro-2-(2-pyridyl)pyrimidines are then reacted, in a suitable solvent, for example dichloromethane, DMF, THF or toluene, with the polymer-bound diamines at from 10 to 120° C. over a period of from 2 to 48 hours. After washing the resin to remove the excess, the target compounds are split off using from 1 to 30% trifluoroacetic acid in dichloromethane at 25° C. over a period of from 1 to 5 hours. For the purpose of further purification, the substances are freeze-dried from tBuOH/water 4:1 with from 1 to 10% HOAc and once from tBuOH/water 4:1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](Br)[CH:6]=1.[CH2:16]([N:18](CC)[CH2:19]C)C.CNC>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N:18]([CH3:19])[CH3:16])[CH:6]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(Br)c1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(N(C)C)c1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
The (3-bromo-4-nitrophenyl)acetic acid methyl ester (0.320 g) obtained in Example 4 b) was dissolved in tetrahydrofuran (10 mL). To this solution were added triethylamine (0.237 g) and dimethylamine (2M tetrahydrofuran; 0.58 mL), and stirred overnight while heating. The reaction mixture was concentrated and purified by column chromatography on silica gel with ethyl acetate:hexane=1:4 to give the title compound (0.145 g) as an orange oil.