Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]([OH:43])[C@H:8]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([C@H:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:36])[O:34][CH3:35])[CH2:23]2)=[O:21])[CH2:9][N:10](C)[C:11](OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl>[CH:1]1([C@H:7]([OH:43])[C@H:8]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([C@H:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:36])[O:34][CH3:35])[CH2:23]2)=[O:21])[CH2:9][NH:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)NCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN(C)C(=O)OC(C)(C)C)[C@@H](O)C2CCCCC2)C1
Solvent: ClCCl
Product: CNC[C@@H](NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2ccccc2)C1)[C@@H](O)C1CCCCC1

Procedure:
A solution of methyl 2-((R)—((R)-1-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate in 20% (V/V) CH2Cl2 (1 mL) was stirred for 1 h. The solution was evaporated under reduced pressure and the residue purified via prep HPLC to afford methyl 2-((R)—((R)-1-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate (1.01 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[O:25])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N+:16]([O-])=O)[C:9]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.C1CCCCC=1>CO.[C].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([NH:13][C:14](=[O:25])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH2:16])[C:9]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)C(c1ccccc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCCC1
Product: NC(C(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)c1ccccc1
Yield: 78.4 %

Procedure:
11 mg of 5-(4-fluorophenyl)-3-(2-nitrophenylacetylamino)-4-(4-pyridyl)pyrazole was dissolved in 5 ml of methanol. Then, 100 mg of cyclohexene and 20 mg of 5% palladium-carbon were added thereto, followed by heating under reflux for 1 hour. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to obtain 8 mg (79% yield) of the title compound as a light-brown powder.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([C:29]2([CH:33]=[O:34])[CH2:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>C1COCC1>[OH:34][CH:33]([C:29]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[CH2:30][CH2:31][CH2:32]1)[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Br
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccnc1C(O)C1(c2cccc(C(F)(F)F)c2)CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 120A (400 mg, 1.465 mmol) in THF (5 mL) was added n-BuLi (3.08 mmol) at −78° C. The resulting solution was stirred at about −78° C. for about 1 hour and then a solution of Example 120C (365 mg, 1.611 mmol) in 10 mL of THF was added. The temperature was warmed to room temperature, stirred for another 1 hour, quenched with 10 mL of water, and extracted with ethyl acetate. The organic layer was washed with brine, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to give the desired crude product, which was used for next step without further purification. LC-MS: m/z (M+H) 439.
Reaction SMILES: Br[C:2]1[O:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12].[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16].C1(NC2CCCCC2)CCCCC1>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[C:16][C:2]1[O:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12]
Reactant: C#CC(C)(C)C
Reactant: CCOC(=O)c1noc(Br)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Product: CCOC(=O)c1noc(C#CC(C)(C)C)c1C
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (100 mg, 0.427 mmol) and 3,3-dimethylbut-1-yne (0.058 mL, 0.470 mmol) in acetonitrile (3 mL) were degassed thoroughly refilling with nitrogen. Dicyclohexylamine (0.085 mL, 0.427 mmol), CuI (2.85 mg, 0.015 mmol) and PdCl2(PPh3)2 (7.50 mg, 10.68 mmol) were added. The mixture was stirred in the microwave at 100° C. for 45 mins. The resulting mixture was adsorbed onto silica and purification by chromatography eluting with 0-10% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1>Cl>[F:18][C:15]([F:16])([F:17])[C:12]1[N:11]=[N:10][C:9]([C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=2)=[CH:14][CH:13]=1
Reactant: COc1cc(-c2ccc(C(F)(F)F)nn2)ccn1
Agent: Cl
Product: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Yield: 110.3 %

Procedure:
3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (115 mg, 0.451 mmol) was stirred in concentrated hydrochloric acid (20 mL) at 120° C. for 18 h and then concentrated. The residue was adjusted to pH 8 with 6 N NaOH and the solids were filtered off, washed with water and dried under vacuum to provide the title compound (120 mg, quant) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.61 (d, J=8.9 Hz, 1H), 8.42 (d, J=8.9 Hz, 1H), 7.62 (d, J=6.8 Hz, 1H), 7.19 (s, 1H), 7.01 (dd, J=6.8, 1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCc2cc(OCCCCCSc3ccc(Cl)c(Cl)c3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCCS(=O)c3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-[5-(3,4-dichlorophenyl-mercapto)-pentoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH:9]=O)[N:7]=1.[C:14]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([CH3:28])[NH2:27])=[CH:21][CH:20]=1)([O:16][CH2:17]C)=[O:15].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>>[C:14]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:27][CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:1])([F:12])[F:13])[S:4][CH:5]=2)[CH3:28])=[CH:21][CH:20]=1)([O:16][CH3:17])=[O:15]
Reactant: O=CC(=O)c1csc(C(F)(F)F)n1
Reactant: CCOC(=O)c1ccc(CC(C)N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Product: COC(=O)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.3 g (0.0062 mol) of 2-(2-trifluoromethyl-thiazol-4-yl)glyoxal and 1.2 g (0.0057 mol) of 2-(4-carboethoxy-phenyl)-1-methyl-ethanamine are mixed at 50° C. and stirred at room temperature for 4 hours. For the reduction of the resulting Schiff's base, 0.75 g of sodium borohydride is added in portions at 20 ° C., and the mixture is stirred for 16 hours. It is then poured onto ice, and the mixture is acidified with hydrochloric acid, made alkaline with sodium bicarbonate solution and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using methylene chloride/methanol =40:1 as eluant.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: COC(=O)c1nn(C)c(=O)cc1Cl
Reactant: Nc1ccccc1F
Product: COC(=O)c1nn(C)c(=O)cc1Nc1ccccc1F
Yield: 61 %

Procedure:
The title compound was prepared in 61% yield by the procedure as previously described in Example 166 (step H) using methyl 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (109 mg, 0.54 mmol, prepared as previously described in Example 1 (steps A-G) and 2-fluoroaniline (0.053 mL, 0.54 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1.O>CN(C=O)C>[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH2:30]1
Reactant: OCC1CCCNC1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCC(CO)C4)cc3)c2)cc1
Reaction time: 72 h
Yield: 65.7 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 3—(hydroxymethyl)piperidine (191 mg). The mixture was starred at room temperature for 72 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[3—(hydroxy-methyl)piperidinomethyl]phenyl]-3—(4-methylphenyl)cinnamamide (Compound 66) (160 mg) as colorless crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:11]2[C:20]([CH3:21])=[CH:19][C:18]3[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=3[CH:12]=2)=[N:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(N(CCCC)CCCC)CCC.[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[CH:40]=[CH2:41]>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[OH:10][NH:9][CH:8]([C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=2[CH:12]=1)[C:4]1[CH:3]=[C:2]([CH:41]=[CH:40][C:39]([O:43][CH2:44][CH3:45])=[O:42])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1cc2c(cc1C(=NO)c1cccc(I)c1)C(C)(C)CCC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: CCOC(=O)C=Cc1cccc(C(NO)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of (3-iodophenyl)-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)methanone oxime (320 mg, 0.7 mmol), palladium diacetate (20 mg, 89 μmol), tributylamine (392 μl, 1.7 mmol) and ethyl acrylate (78 μl, 0.7 mmol) in acetonitrile (10 ml) is heated for 4 h at 80° C. The reaction medium is extracted with ethyl ether and washed with water. After drying, the organic phase is concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash- chromatography on a column of silica.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:25](=N)[N:24]([CH2:27][CH3:28])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1.C(OC(=O)C)(=[O:31])C.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:25](=[O:31])[N:24]([CH2:27][CH3:28])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCn1c(=N)c(-c2c(Cl)cccc2Br)cc2cnc(Nc3ccccc3)nc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Br)cc2cnc(Nc3ccccc3)nc21

Procedure:
(6-(2-Bromo-6-chlorophenyl)-8-ethyl-7-imino-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine (150 mg) was added to 1 mL of acetic anhydride and heated at reflux for 5 minutes. The reaction was cooled and concentrated resulting in an oil which was heated at reflux with 10 mL of 6N HCl for 10 minutes. The reaction was cooled, and 30 mL of water was added causing precipitation. The precipitate was removed by filtration and washed with water. The resulting solid was dried to give 130 mg of 6-(2-bromo-6-chlorophenyl)-8-ethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one; mp softens at 195° C. and melts at 210°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:42][CH:43]=[CH:44][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][C:10]([NH:13]C(=O)OC(C)(C)C)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:13][C:10]([CH3:12])([CH3:11])[CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)=[CH:33][N:32]=[C:31]3[NH:42][CH:43]=[CH:44][C:30]=23)[CH2:25][CH2:24]1)=[O:22]
Reactant: CC(C)(C[C@@H](C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C[C@@H](C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
(R)-tert-Butyl 4-(4-chlorophenyl)-5-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-methyl-5-oxopentan-2-ylcarbamate (0.026 g, 0.042 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid product was collected by filtration, washed with ether, and dried to give (R)-4-amino-2-(4-chlorophenyl)-1-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-4-methylpentan-1-one (0.019 g, 76% yield) as the dihydrochloride salt. MS ESI (+) m/z 521 detected.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:16])=O)=[CH:7][N:8]2[CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][NH:24][CH3:25].O>ClC(Cl)C.CN(C=O)C>[CH3:23][N:24]([CH3:25])[C:14]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]#[N:13])[CH:7]=1)=[O:16]
Reactant: CNC
Reactant: N#CCn1cc(C(=O)O)c2ccc(Br)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cn(CC#N)c2cc(Br)ccc12
Reaction time: 24 h
Yield: 63 %

Procedure:
To a suspension of 6-bromo-1-cyanomethyl-1H-indole-3-carboxylic acid (0.478 g, 1.71 mmole) in dichloroethane (100 ml) was added oxalyl chloride (2.6 g, 20.55 mmole) at room temperature followed by a few drops of anhydrous DMF. The reaction was stirred at the same temperature for 24 h. To this mixture was added dimethyl amine (21.4 ml, 2 N in THF, 42.8 mmole) slowly. The reaction mixture was then poured into water (200 ml) and the organic phase was separated, evaporated to dryness and the residue was purified by column chromatography (silica gel, hexane:ethyl acetate 1:1). The pure product weighed 0.335 g (63% yield).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:46]=[CH:45][N:14]3[C:15](=[O:44])[C:16](/[CH:25]=[CH:26]/[C:27]([NH:29][S:30]([CH2:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)(=[O:32])=[O:31])=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:46]=[CH:45][N:14]3[C:15](=[O:44])[C:16](/[CH:25]=[CH:26]/[C:27]([NH:29][S:30]([CH2:33][CH2:34][CH2:35][NH2:36])(=[O:32])=[O:31])=[O:28])=[C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)NS(=O)(=O)CCCNC(=O)OC(C)(C)C)c(N4CCOCC4)nc3c2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)NS(=O)(=O)CCCN)c(N4CCOCC4)nc3c2)n1
Reaction time: 0.67 h

Procedure:
The N-((E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido -[1,2-a]pyrimidin-3-yl}-2-propenoyl)-3-(tert-butoxycarbonylamino)-1-propane -sulfonamide (32 mg) obtained in (A) was dissolved in trifluoroacetic acid (2 ml) and stirred for 40 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure reverse phase column chromatography to obtain the title compound (quantitative).
Reaction SMILES: [CH2:1]1[CH:9]([CH2:10][C:11]([OH:13])=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N(CC)CC)C.Cl.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(OP(C#N)(=O)OCC)C>C(Cl)Cl>[CH:9]1([CH2:10][C:11]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[O:13])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CC1CCc2ccccc21
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)CC3CCc4ccccc43)CC2)cc1
Reaction time: 3 h

Procedure:
A mixture of 1-indanylacetic acid (CIX, EXAMPLE 66, 7.4 g, 42 mmol) and triethylamine (29.3 ml, 210 mmol), and 1-(4-methoxyphenyl)piperazine dihydrochloride (LXV, 13.3 g, 50.4 mmol) in methylene chloride (420 ml) is stirred at 20-25° under a nitrogen atmosphere. Diethylcyanophosphonate (12.7 ml, 84 mmol) is added over a period of 10 min at 20-25°. After the stirring for 3 hr, the reaction is quenched with sodium hydroxide (20%) and extracted with methylene chloride (2×500 ml). The organic phase is washed with saline, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified by crystallization from ethyl acetate/methanol. The mother liquor is purified by liquid chromatography on silica gel 60 (230-400 mesh, 400 g), eluting with hexane/ethyl acetate (1/2). The appropriate fractions homogeneous by TLC are combined and concentrated under reduced pressure to give a solid. Both solids are combined to give the title compound, mp=111-112°; NMR (CDCl3, TMS) 7.26-6.83, 3.77 and 3.85-1.54 δ.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(Cl)cc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,4-Dichloro-benzoic acid.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[C:7]=1[NH2:8]
Reactant: NCC1CCOCC1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1c(Cl)ncnc1NCC1CCOCC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
Charge a microwave reaction vial with 4,6-dichloro-pyrimidin-5-ylamine (12.20 mmoles, 2.00 g), isopropyl alcohol (5 mL), C-(tetrahydro-pyran-4-yl)-methylamine (14.63 mmoles, 1.69 g), and N,N-diisopropylethylamine (15.85 mmoles, 2.76 mL). Irradiate with stirring at 140° C. for 2 hours with high absorbance mode in the microwave. Solvent is evaporated and residue triturated with dichloromethane to afford 6-Chloro-N*4*-(tetrahydro-pyran-4-ylmethyl)-pyrimidine-4,5-diamine
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[N:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:39][CH:38]=3)=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccc(-c3ccc(N4CCN(C)CC4)nc3)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 49.3 %

Procedure:
To a 5 mL microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 31 mg, 0.073 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (22.16 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (4 ml) and acidified with 1N HCl (1 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[5-hydroxy-6-(1-methylethyl)-2-({4-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (23 mg, 0.036 mmol, 49.7% yield) as a white powder tfa salt. 1H NMR (400 MHz, DMSO-d6) d ppm 15.87 (s, 1H), 10.19 (t, J=5.68 Hz, 1H), 9.94 (s, 1 H), 8.48 (d, J=2.53 Hz, 1H), 7.94 (dd, J=9.09, 2.53 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2 H), 7.06 (d, J=9.09 Hz, 1H), 5.28 (s, 2H), 4.47 (d, J=13.39 Hz, 2H), 4.10 (d, J=5.56 Hz, 2H), 3.53 (dd, J=10.23, 6.44 Hz, 2H), 2.99-3.26 (m, 5H), 2.85 (s, 3H), 1.22 (d, J=6.82 Hz, 6H). MS (ES+) m/e 521 [M+H]+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[C:11]2[N:13](C(=O)C3C=CC=CC=3)[CH:14]=[CH:15][C:10]2=[CH:9][CH:8]=1)(C)C.[OH-].[Na+]>CO>[C:6]([C:7]1[N:12]=[C:11]2[NH:13][CH:14]=[CH:15][C:10]2=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2ccn(C(=O)c3ccccc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
The synthesis was performed with reference to the known literature (Bulletin of Chemical Society of Japan, Vol. 65, p. 2992, 1992). A solution of 6-[(trimethylsilyl)ethynyl]-1-benzoyl-1H-pyrrolo[2,3-b]pyridine (0.039 g, 0.12 mmol) in methanol (2.0 mL) was added with 5 N aqueous sodium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with a mixed solvent of hexane and ethyl acetate to obtain 6-ethynyl-1H-pyrrolo[2,3-b]pyridine (0.016 g, 90%).