Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[NH2:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[NH2:12][C:13]1[C:18]([O:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])=[N:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1ccccc1CO
Reactant: Nc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1COc1nccnc1N
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of 2-methylbenzyl alcohol (0.985 g) in N,N-dimethylformamide (10 ml) was added 62.8% sodium hydride (0.308 g) under a nitrogen atmosphere and then stirred for 30 minutes. 2-Amino-3-chloropyrazine (0.87 g) was added to the solution and the mixture was heated at 65° C. for 2 hours and poured onto crushed ice. The resulting precipitates were collected by filtration, washed with n-hexane, and dried in a desiccator to give 2-amino-3-(2-methylbenzyloxy)pyrazine (0.6 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>C(O)CCC>[C:14]1([C:4]2[N:3]=[C:2]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=3)[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CSc1ccc(N)cc1
Solvent: CCCCO
Product: CSc1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1

Procedure:
4-Chloro-2,6-diphenyl-pyrimidine (0.4 g, 1.5 mmol) was reacted with 4-methylsulfanyl-phenylamine (0.22 g, 1.6 mmol) in a solvent n-butanol (10 mL) at reflux temperature for 12 hours to yield (2,6-diphenyl-pyrimidin-4-yl)-(4-methylsulfanyl-phenyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=2)[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH:16]4[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(C2CC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(C3CC3)nc2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-cyclopropyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:41]([CH3:42])=[CH:40][C:5]2[N:6]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]([CH:9]([OH:20])[C:10]3[C:11]([F:19])=[C:12]([OH:18])[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=3)=[N:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:50][CH3:51]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[C:41]([CH3:42])=[CH:40][C:5]2[N:6]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]([CH:9]([C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([O:18][CH2:50][CH3:51])[C:11]=3[F:19])[OH:20])=[N:8][C:4]=2[CH:3]=1
Reactant: CCI
Reactant: CCc1cc(O)c(F)c(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CC)cc(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of this phenol (34 mg, 0.061 mmol) in 2 mL DMF, were added K2CO3 (10 mg, 0.073 mmol) and iodoethane (15 μL, 0.18 mmol). The mixture was stirred at rt for 16 h, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 35.7 mg of Intermediate 415.3. LCMS (2 min gradient) RT=1.97 min, 585.47 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:18][N:17]([CH3:19])[S:14]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:3]1[CH2:2][NH:1][C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)(=[O:15])=[O:16]
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CN
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CNc1cnc2ccccc2n1
Temperature: 180 °C

Procedure:
2-(Aminomethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (0.56 mmol), 2-chloroquinoxaline (138 mg, 0.84 mmol), and Hunig's base (195 μL, 1.12 mmol) were dissolved in anhydrous THF (4.5 mL) in a microwave vial. The vial was heated in the microwave (180° C., 40 min), then poured into saturated aqueous K2CO3 solution (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were washed with saturated aqueous NaCl (1×50 mL), dried (Na2SO4), filtered and concentrated to give N,N-dimethyl-4-phenyl-2-((quinoxalin-2-ylamino)methyl)-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[CH2:10]([C:15]12[CH2:22][CH2:21][C:18]([C:23]([OH:25])=O)([CH2:19][CH2:20]1)[CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][CH3:14].Cl.CN>C(Cl)Cl>[CH3:1][NH:4][C:23]([C:18]12[CH2:21][CH2:22][C:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:20][CH2:19]1)[CH2:16][CH2:17]2)=[O:25]
Reactant: CCCCCC12CCC(C(=O)O)(CC1)CC2
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CCCCCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (1.44 mL, 11.1 mmol) was added to a mixture of 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid (3-A) (1.09 g, 4.45 mmol) and methylamine hydrochloride (1.5 g, 22.3 mmol) in methylene chloride (10 mL) was added and the mixture stirred at room temperature for 18 h. After diluting with methylene chloride, the mixture was washed with water, brine, dried (MgSO4) and concentrated in vacuo to give N-methyl-4-pentylbicyclo[2.2.2]octane-1-carboxamide (3-C). 1H NMR (500 MHz, CDCl3): δ 0.91 (t, 3H); 1.22 (m, 8H); 1.43 (m, 6H); 1.77 (m, 6H); 2.82 (d, 3H) ppm.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.BrC[CH:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[N:56]=[C:55]([C:57]3[C:61]([CH2:62][CH2:63][CH3:64])=[C:60]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[O:59][N:58]=3)[O:54][N:53]=2)=[CH:48][CH:47]=1)[OH:45]>C(Cl)Cl>[OH:45][CH:44]([C:46]1[CH:47]=[CH:48][C:49]([C:52]2[N:56]=[C:55]([C:57]3[C:61]([CH2:62][CH2:63][CH3:64])=[C:60]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[O:59][N:58]=3)[O:54][N:53]=2)=[CH:50][CH:51]=1)[CH2:6][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC[C@H]4CC(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (45.4 mg, 0.198 mmol) in DCM was added TFA. The reaction mixture was stirred for 1 hour followed by the removal of solvents in vacuo and drying of the solid material. Next, DMSO (2 mL) was added followed by the addition of tetrabutylammonium hydroxide (0.198 mL, 0.198 mmol) and then 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 30-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 9 mg of 2-((2S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)pyrrolidin-2-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.18 (4H, d, J=8.35 Hz), 7.77-7.84 (2H, m), 7.54-7.67 (5H, m), 5.92-6.01 (1H, m), 5.00-5.09 (2H, m), 4.26-4.42 (1H, m), 3.76-3.94 (1H, m), 3.00-3.11 (2H, m), 2.75-2.98 (2H, m), 2.18-2.34 (1H, m), 1.90-2.14 (2H, m), 1.60-1.85 (3H, t, J=7.25 Hz). MS (m+1)=503. HPLC Peak RT=3.50 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [OH:1][C@H:2]([C:20]1[CH:21]=[CH:22][C:23]([NH:26]C(=O)C)=[N:24][CH:25]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C.O>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C@@H:2]([OH:1])[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[CH:10][CH:9]=2)=[CH:21][CH:22]=1
Reactant: CC(=O)Nc1ccc([C@@H](O)CNCCOc2ccc(-c3csc(C)n3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(OCCNC[C@H](O)c3ccc(N)nc3)cc2)cs1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
In a round-bottomed flask, (R)-N-[5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide (74 mg, 0.18 mmol) was dissolved in 1.0 mL of ethanol, and 1.0 mL of 2 M sodium hydroxide was added to the solution. The reaction mixture was then heated to about 80° C. for about twenty minutes, and was then diluted with water and adjusted to about pH 11. The aqueous phase was extracted with four portions of methylene chloride, and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography (methylene chloride to 20% methanol/methylene chloride) to afford 49 mg (74%) of the desired product. LRMS ([M+1]+): 371.2.
Reaction SMILES: O.O.O.[F:4][C:5]([F:13])([F:12])[C:6]([C:8]([F:11])([F:10])[F:9])=[O:7].[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:4][C:5]([F:13])([F:12])[C:6]([C:20]1[CH:19]=[C:18]([CH3:22])[C:16]([NH2:17])=[C:15]([CH3:14])[CH:21]=1)([OH:7])[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Temperature: 130 °C
Reaction time: 14 h
Yield: 87 %

Procedure:
Hexafluoroacetone trihydrate (9.68 g, 44 mmol) was added to 2,6-dimethylaniline (4.84 g, 40 mmol) and p-toluenesulfonic acid (304 mg, 1.6 mmol) at room temperature. The mixture was stirred at 130° C. for 14 hours under a nitrogen atmosphere. After cooling down, the solidified mixture was washed with sodium bicarbonate solution, water, and hexane and dried to afford 10 g of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,6-dimethylaniline. 1H NMR (DMSO): δ 8.11 (s, 1H), 7.08 (s, 2H), 4.89 (s, 2H), 2.10 (s, 6H). MS (ES) m/z 288.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:36](O)=[O:37]>>[CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:36]=[O:37]
Reactant: COc1c(C)c(Cc2ccccc2O)c(OC)c(OC)c1OC
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C)c(Cc2cccc(C=O)c2O)c(OC)c(OC)c1OC
Temperature: 80 °C
Yield: 27 %

Procedure:
2-(3,4,5,6-Tetramethoxy-2-methylbenzyl)phenol (8.64 g, 27.17 mmol) and hexamethylenetetramine (5.00 g, 35.67 mmol) were dissolved in trifluoroacetic acid (100 ml) and the solution was stirred under heating at 80° C. for 4 hours. After the completion of reaction, the solvent was removed by distillation and to the obtained residue, water (100 ml) was added. The resulting solution was stirred for 30 minutes and extracted with methylene chloride. The extract was washed with water and then dried, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (2.50 g, 7.23 mmol, 27%).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C([O:6][C:7](=O)[NH:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[CH:10][C:11]#[N:12])C.[CH3:22][CH:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH:33][NH2:34])=O)[CH2:27][CH2:26]1)[CH3:24].O>CN1CCCC1=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:9]1[NH:8][C:7](=[O:6])[N:34]2[N:33]=[C:31]([CH:28]3[CH2:29][CH2:30][N:25]([CH:23]([CH3:24])[CH3:22])[CH2:26][CH2:27]3)[N:12]=[C:11]2[CH:10]=1
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
In a round-bottom flask fitted with reflux condenser and a drying tube filled with calcium chloride, 500 mg (1.70 mmol) of ethyl[2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate and 310 mg (1.70 mmol) of 1-(1-methylethyl)piperidin-4-carbohydrazide (Example 38A) were dissolved in 2 ml of 1-methyl-2-pyrrolidone, and the reaction mixture was stirred at 160° C. for 3 h. The reaction solution was cooled to 100° C., water (20 ml) was added and the mixture was then cooled to RT and stirred for 15 min. The reaction mixture was extracted with dichloromethane (3×50 ml), and the combined organic phases were dried over magnesium sulfate and concentrated. The crude product was chromatographed on basic aluminum oxide (mobile phase dichloromethane/methanol 10:1, then dichloromethane/methanol/17% strength aqueous ammonia solution 15:2:0.2). This gave 2.55 g (78% of theory) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@@H:7]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:6][C:5]2=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=1>>[CH2:22]([N:11]1[C:10]2[CH2:9][CH2:8][C@@H:7]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)C(=O)N[C@@H]1CCc2[nH]c3ccc(Br)cc3c2C1
Reactant: Fc1cccc(CBr)c1
Product: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(Br)ccc3n2Cc2ccccc2)C1

Procedure:
Alkylate (R)-N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide with 1-bromomethyl-3-fluorobenzene using procedures essentially as described in Example 1 to give the title compound. MS (ES): m/z 443 (M+1), 445 (M+1+2); m.p.=204-207° C. (Alkylate the S isomer in a similar fashion to obtain (S)-N-(9-Benzyl-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide.)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([N:14]3C(=O)C4=CC=CC=C4C3=O)[C:10]([CH3:25])=[N:9]2)=[CH:6][CH:7]=1.C(O)C.O.NN>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([NH2:14])[C:10]([CH3:25])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nn(-c2ccc(Cl)nn2)c(C)c1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nn(-c2ccc(Cl)nn2)c(C)c1N

Procedure:
A mixture of 3.54 g (0.01 moles) of 3-chloro-6-(3,5-dimethyl-4-phthalimido-1-pyrazolyl)-pyridazine, 40 ml of ethanol and 1.08 g (0.01 moles) of 98% hydrazine hydrate is heated to reflux for 3 hours and the mixture is poured into 100 ml of water. After cooling the precipitated crystals are filtered, washed with water, triturated with 10 ml of hot ethanol, filtered and dried. Yield: 1.8 g (81%); m.p. 165°-168° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:7]1[C:2]2[NH:1][C:13](=[O:14])[CH2:12][O:10][C:3]=2[C:4]([F:9])=[CH:5][CH:6]=1
Reactant: Nc1c(F)ccc(F)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)ccc(F)c2N1
Yield: 93.6 %

Procedure:
2-Amino-3,6-difluorophenol (0.44 g, 3.0 mmol), 2-chloroacetyl chloride (0.38 g, 3.3 mmol) and K2CO3 (0.88 g, 6.4 mmol) were mixed according to GP1. Purified by extraction gave the title compound (0.52 g, 93%). Rf=0.57 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.78-6.69 (m, 2H), 4.72 (s, 2H); 13C NMR (CDCl3) δ 163.7, 148.0 (dd, J=242.4 Hz, J=2.1 Hz), 145.9 (d, J=237.9 Hz), 132.9 (dd, J=16.7 Hz, J=4.4 Hz), 117.2 (dd, J=16.9 Hz, J=3.8 Hz), 110.2 (dd, J=20.5 Hz, J=8.6 Hz), 108.6 (dd, J=20.0 Hz, J=7.7 Hz), 67.4.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]([CH3:29])=[CH:7][CH2:8][C:9]1[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[OH-].[Na+].Cl>CO.O>[CH3:19][O:18][C:17]1[C:16]([CH3:20])=[C:15]2[C:11]([C:12](=[O:21])[O:13][CH2:14]2)=[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:9]=1[CH2:8][CH:7]=[C:6]([CH3:29])[CH2:5][CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CCC(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A mixture of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester (1.5 g, 3.45 mmol) and sodium hydroxide (552 mg) in a mixture of methanol (20 mL) and water (7 mL) was stirred at room temperature for one hour. The solution was acidified with 1N HCl. The precipitate was collected by suction filtration and washed with water to give the desired product (1.2 g, 83%). 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 1.15-1.22 (m, 2H), 1.76 (s, 3H), 2.13 (s, 3H), 2.12-2.28 (m, 2H), 2.35-2.41 (m, 2H), 3.37 (d, 2H, J=7 Hz), 3.71 (s, 3H), 4.22-4.28 (m, 2H), 5.07 (s, 2H), 5.13-5.17 (m, 1H) ppm; MS (m/z) 419.3 [M−H]−, 443.2 [M+Na]+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (20 mg, 0.043 mmol) in Acetonitrile (0.5 mL) was treated with 4-fluorobenzyl chloride (0.025 mL, 0.213 mmol) and Cs2CO3 (69 mg, 0.213 mmol) and then stirred at 70° C. for 2 hours. The mixture was diluted with water and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(4-fluorobenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate as pale a yellow solid which was used with no further purification. LCMS (m/z) ES+=511 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])[C:9](=[O:19])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([NH2:28])[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:2]2[C:3]3[C:10](=[CH:11][C:12]4[CH:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[N:13]=4)[C:9](=[O:19])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ncnc(Cl)c32)[nH]1
Product: CC1=CC(C)C(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)=N1
Yield: 57 %

Procedure:
The title compound (57% yield) was prepared from 4-chloro-5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 3chloro-4-fluoro-phenylamine according to the procedure described for Example 12 without the conversion to the HCl salt. 1H NMR (360 MHz, DMSO-d6) δ 313.10 (br s, 1H, NH), 11.60 (br s, 1H, NH), 9.10 (s, 1H), 8.27 (s, 1H, H-vinyl), 7.70 (m, 1H), 7.3-7.4 (m, 3H), 6.04 (br s, 1H), 2.33 (s, 3H, CH3), 2.16 (s, 3H, CH3) MS 384.3 [M++1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25]([OH:29])(=[O:28])[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C=O)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:27]=[CH:26]/[C:25]([OH:29])=[O:28])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 100 °C

Procedure:
A mixture of the title compound of Example 5 (0.913 g), acrylic acid (0.17 mL), palladium acetate (4 mg) and triethylamine (0.70 mL) in 5 mL DMF is heated to 100° C. for 24 h in a pressure-safe tube. The reaction is cooled and diluted with 50 mL of a 10% aqueous HCl solution. The resulting solid is collected, dried and recrystallized from EtOH to yield 0.564 g of the desired product as a tan solid.
Reaction SMILES: [C:1](OC(N1CC(C(O)=O)C1)=O)(C)(C)[CH3:2].[C:15]([O:19][C:20]([N:22]1[CH2:25][CH2:24][CH:23]1[C:26]([OH:28])=[O:27])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH2:24][C:23]1([CH2:1][CH3:2])[C:26]([OH:28])=[O:27])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Product: CCC1(C(=O)O)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the procedure described for Reference Example 15 substituting 1-tert-butoxycarbonylazetidine-3-carboxylic acid with 1-tert-butoxycarbonylazetidine-2-carboxylic acid at Step A. 1H NMR (500 MHz, CD3OD): δ 3.98-3.90 (m, 1H), 3.80-3.62 (m, 1H), 2.36-1.82 (m, 4H), 1.42 (s, 9H), 1.02 (t, 3H).