Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[C:16]([CH:19]=[C:20]=[O:21])(=[O:18])[CH3:17]>CCOC(C)=O>[F:15][C:7]1[CH:6]=[C:4]([NH:5][C:20](=[O:21])[CH2:19][C:16](=[O:18])[CH3:17])[CH:3]=[C:2]([F:1])[C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CC(=O)C=C=O
Reactant: Nc1cc(F)c(N2CCOCC2)c(F)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 83 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 3,5-difluoro-4-morpholinoaniline (3.42 g, 16.0 mmol) and acetyl ketene (1.61 g, 19.2 mmol) in EtOAc (20 mL) was stirred at 83° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (3.10 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[N:30](S(C4C=CC(C)=CC=4)(=O)=O)[CH:31]=[CH:32][C:25]=23)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[NH:30][CH:31]=[CH:32][C:25]=23)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCN[C@H](C)C6)nn45)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc5[nH]ccc45)n3n2)CCN1
Temperature: 60 °C
Yield: 91.2 %

Procedure:
Added to a solution of 0.230 g (0.40 mmol) of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine obtained in step 3.3, in 5 ml of methanol, is 0.13 ml (0.76 mmol) of a 6N aqueous solution of sodium hydroxide. The mixture is heated at 60° C. for 30 minutes then poured into 100 ml of water. The product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The residue obtained is recrystallized in acetonitrile in order to give 0.156 g of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine after drying.
Reaction SMILES: [O:1]=[C:2]1[CH:10](SC)[C:9]2[C:4](=[C:5]([Cl:20])[CH:6]=[CH:7][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3]1>[Ni].O1CCOCC1>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:20])[CH:6]=[CH:7][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3]1
Reactant: CSC1C(=O)Nc2c(Cl)ccc(Oc3ccccc3)c21
Agent: [Ni]
Solvent: C1COCCO1
Product: O=C1Cc2c(Oc3ccccc3)ccc(Cl)c2N1
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
2-Oxo-3-methylthio-4-phenoxy-7-chloroindoline (6 g) was added to a mixture of Raney nickel (15 ml) and dioxane (80 ml), and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was allowed to stand at room temperature, and the supernatant was separated by decantation. To the residue was added dioxane (50 ml), and the supernatant was separated again. The dioxane solution was combined and filtered. The filtrate was evaporated in vacuo, and the residue was washed with diethyl ether and dried to give 2-oxo-4-phenoxy-7-chloroindoline (4.3 g). mp. 200°-202° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH2:26])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[C:32]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)[CH:36]=[CH:37][CH:38]=2)=[N:31][N:30]=[N:29]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:32]2[N:28]([CH3:27])[N:29]=[N:30][N:31]=2)[CH:34]=1)=[O:41])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1N
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCCC[C@H]2CN(CCCc2ccc(F)cc2)C(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 25.1 %

Procedure:
The product of Step i (0.26 g, 0.69 mmol, 1 eq.), and phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate (Example 1a, see below)(0.20 g, 0.69 mmol, 1 eq.) were dissolved in DMF (2 mL) at room temperature and stirred under N2 overnight. The DMF was stripped on the rotary evaporator and EtOAc was added (50 mL). This mixture was washed with water (3×50 mL), dried (MgSO4), stripped, and flash chromatographed in 3:1 Hexanes/EtOAc to 1:1 Hexanes/EtOAc to 100% EtOAc to yield 98 mg of a white glass. MS (AP+) detects (M+H)+=566.6.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)=[O:18])[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: OC1CCNCC1
Product: CON=C1C[C@@H](C(=O)N2CCC(O)CC2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-piperidinol, the title compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=422.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([NH2:44])(=[S:43])[CH3:42].C(N(C(C)C)CC)(C)C>ClCCl>[C:41]([NH:44][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16])(=[S:43])[CH3:42]
Reactant: CC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=S)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (2.213 g, 9.65 mmol), HATU (4.050 g, 10.65 mmol) and thioacetamide (1.597 g, 21.26 mmol) were mixed in anhydrous dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 30 min. N,N-diisopropyl-N-ethylamine (5.3 mL, 30.3 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solution was concentrated and the crude residue was purified on SiO2 (10 to 60% ethyl acetate, hexanes) to afford the title compound, which was used without further purification. HPLC/MS: 112.1 (M−174), Rt=3.00 (LC4).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=4)[NH:22][CH:21]=3)[C:28]([C:30]3[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: Cn1cc(C#N)cc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C#N)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-methyl-1H-indole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile. Mass: 470.26 (M+H).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C(N(CC)CC)C.C(OCC)(=O)C[SH:21].[CH3:26][CH2:27][O:28][CH2:29][CH3:30]>>[CH2:27]([O:28][C:29](=[S:21])[CH2:30][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH3:26]
Reactant: CCOC(=O)CS
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=S)CC(C[N+](=O)[O-])c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of beta-nitrostyrene (447 mg) in ether (10 ml) are added triethylamine (42 l) and ethyl thioglycolate (0.33 ml). After 30 minutes' stirring, the mixture is concentrated to give (1-phenyl-2-nitroethyl)thioacetic acid ethyl ester (718 mg).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:27]>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26]([N:11]2[CH2:12][C@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]2[C:8](=[O:9])[NH:7][C:4]2([C:2]#[N:3])[CH2:6][CH2:5]2)=[O:27])=[CH:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)Oc2ccc(F)cc2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with 4-fluorophenyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid 4-fluoro-phenyl ester as a colorless oil. MS: 492.1 [M+H]+.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([N:19]1[CH2:26][C@H:25]([OH:27])[CH2:24][C@H:20]1[C:21]([OH:23])=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[CH3:35][C:36]1[C:41]([C:42]([OH:44])=[O:43])=[C:40]([NH:45][C:46](=[O:52])[C@H:47]([CH:49]([CH3:51])[CH3:50])[NH2:48])[CH:39]=[CH:38][CH:37]=1.C(OC(N1CCC[C@H]1C(N[C@@H](C(NC1C=CC=C(C)C=1C(O)=O)=O)C(C)C)=O)=O)C1C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:26][C@H:25]([OH:27])[CH2:24][C@H:20]1[C:21]([NH:48][C@H:47]([C:46]([NH:45][C:40]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:35])[C:41]=1[C:42]([OH:44])=[O:43])=[O:52])[CH:49]([CH3:51])[CH3:50])=[O:23])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1cccc(NC(=O)[C@H](NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Isobutyl chloroformate (0.23 ml) was added to a tetrahydrofuran solution (3.5 ml) containing N-benzyloxycarbonyl-trans-4-hydroxy-L-proline (463 mg) and N-methylmorpholine (0.19 ml) at -15° C., and the mixture was stirred for 0.5 hour. An N,N-dimethylformamide solution (2.5 ml) containing 6-methyl-2-(L-valylamino)benzoic acid (291 mg) and N-methylmorpholine (0.15 ml) was added dropwise to the above mixture at -15° C., and the resultant mixture was stirred at -15° C. for 0.5 hour and then at room temperature for two hours. The reaction mixture was treated by the same procedures as in item (c) of Example 1 to obtain 2-[(N-benzyloxycarbonyl-trans-4-hydroxy-L-prolyl)-L-valyl]amino-6-methylbenzoic acid (570 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1([S:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([NH2:71])[CH:66]=2)(=[O:58])=[O:57])[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C=O)C>[N:50]1([S:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([NH:71][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:66]=2)(=[O:58])=[O:57])[CH2:51][CH2:52][O:53][CH2:54][CH2:55]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccccc4S(=O)(=O)N4CCOCC4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 73.6 %

Procedure:
DIEA (0.009 mL, 0.052 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.010 g, 0.047 mmol) and HATU (0.020 g, 0.052 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-(Morpholine-4-sulfonyl)-biphenyl-3-ylamine (0.015 g, 0.047 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 73% yield: LCMS (ESI) m/z 521 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[C:12]([NH:14][C@H:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[CH3:16])=[O:13])=[CH:4][CH:3]=1.O[Li:30].O>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[C:12]([NH:14][C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH3:16])=[O:13])=[CH:4][CH:3]=1.[Li+:30]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2ccc(F)cc2)cc1
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CCCN1Cc1ccc(F)cc1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E28) (13 mg) was prepared according to the general procedure for esters hydrolysis (Method A) starting from methyl 4-((S)-1-((R)-1-(4-fluorobenzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D145) (22 mg). (LiOH H2O: 1.2 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35]Cl)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1>[ClH:21].[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35][N:12]2[CH2:13][CH2:14][CH:9]([C:7]([OH:8])([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: OC(c1ccccc1)(c1ccc(Cl)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 93 h

Procedure:
A mixture of 11 g (0.035 mole) of α-phenyl-α-(p-chlorophenyl)-4-piperidinemethanol, 12.5 g (0.05 mole) of 4'-tert-butyl-4-chlorobutyrophenone, 10 g of potassium bicarbonate, 0.1 g of potassium iodide, 100 ml of toluene and 10 ml of water is refluxed with stirring for about 93 hours. Upon cooling to room temperature the mixture is filtered and the toluene layer is separated. The aqueous layer is extracted with toluene. The combined organic fractions are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and filtered. To the filtrate is added an equal volume of ether followed by treatment with ethereal HCl. The resulting precipitate is collected and recrystallized from methanol-butanone to give 4'-tert-butyl-4-[4-[α-hydroxy-α-(p-chlorophenyl)benzyl]-piperidino]butyrophenone hydrochloride, M.P. 238.5°-240°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[C:16]([NH2:17])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>C1COCC1>[NH2:17][C:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH:36][C:27]4[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=4[F:25])=[O:38])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[NH:14][N:15]=1
Reactant: Nc1ccc(-c2ccc3c(N)n[nH]c3n2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1n[nH]c2nc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.44 mmol) of 6-(4-aminophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine are partially solubilized in 2.5 ml of anhydrous THF. The mixture is then degassed for 15 minutes with argon. 61.55 μl (44.93 mg, 0.44 mmol, 1 eq.) of triethylamine are subsequently added. The solution is once again degassed for 15 minutes. Finally, 64.22 μl (91 mg, 0.44 mmol, 1 eq.) of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate are added dropwise. The mixture is stirred for 2 hours at ambient temperature under an inert atmosphere. After reaction, the mixture is filtered. The filtrate is concentrated. A beige solid is isolated. This crude product is subsequently purified on a C18 reverse-phase silica (13 g) column with an eluent gradient of 5% to 95% of acetonitrile in water. The fractions containing the expected product are lyophilized. A white solid is isolated (10 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.C[O:23]B(OC)OC.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][C:7]=1[OH:23]
Reactant: CCCc1ccc(-c2cccc(F)c2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(O)c(F)c2)cc1
Temperature: -74 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
In a nitrogen atmosphere, 44.32 g of 3-fluoro-1-(4-propylphenyl)benzene was dissolved in 220 mL of THF, the resultant solution was cooled to −74° C., and 210 mL of secondary butyl lithium (1.0 mol/L, hexane solution) was added at such a rate that the inside temperature did not exceed −60° C. After stirring at −74° C. for 1 hour, 23.64 g of trimethoxyborane was added at such a rate that the inside temperature did not exceed −60° C. After stirring at −74° C. for 1 hour, the inside temperature was increased to room temperature, and 10% hydrochloric acid was added until the system became acidic. Then, an organic layer was separated, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and cooled with ice, and 54 g of a 15% aqueous hydrogen peroxide solution was added to the mixture, followed by stirring under ice cooling for 3 hours. Further, an organic layer was separated, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and washed with a 10% aqueous sodium sulfite solution and saturated brine. The organic layer mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to yield 41.01 g of 2-fluoro-4-(4-propylphenyl)phenol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[CH3:20][N:21]([CH:23]=O)[CH3:22]>>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:1]/[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:5]=[C:4]([S:18][CH3:19])[N:3]=1
Reactant: CSc1nc(C)c(C#N)c(Nc2cccc(C)c2)n1
Reactant: CN(C)C=O
Product: CSc1nc(/C=C/N(C)C)c(C#N)c(Nc2cccc(C)c2)n1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-methyl-6-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile (1.32 g, 4.89 mmol) in DMF (8 mL) was added DMF dimethyl acetyl (1.16 g, 9.75 mmol), and the reaction mixture was stirred at 110° C. for 1.5 h. The mixture was concentrated and the residue was dissolved into EtOAc (30 mL). The solution was washed with water and organic layer was collected. The aqueous layer was extracted with EtOAc (2×). The combined extract was dried over Na2SO4, filtered, and concentrated to give the crude enamine product (1.47 g). MS: M(C17H19N5S)=325.44, (M+1)+=326.1
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]([O:12]CC)=O)=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1)(=O)[CH3:2].[CH3:17][NH:18][NH2:19]>C(O)CCC>[CH3:17][N:18]1[C:10](=[O:12])[C:9]2[CH:8]=[N:7][C:6]([S:15][CH3:16])=[N:5][C:4]=2[C:1]([CH3:2])=[N:19]1
Reactant: CCOC(=O)c1cnc(SC)nc1C(C)=O
Reactant: CNN
Solvent: CCCCO
Product: CSc1ncc2c(=O)n(C)nc(C)c2n1
Temperature: 25 °C

Procedure:
A solution of Example 1B (600 mg, 2.497 mmol) and methylhydrazine (0.131 mL, 2.497 mmol) in n-butanol (12.5 mL) was heated to 140° C. by microwave irradiation (Biotage Initiator) for 30 minutes. The reaction mixture was cooled to room temperature, whereupon a solid crystallized from the solution. The solid was filtered, washed with hexane, and air-dried to provide the title compound. MS ESI(+) m/z 223 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH:25][C:43]([C:40]5[C:41](=[O:42])[N:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)[N:37]=[CH:38][CH:39]=5)=[O:44])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A 100 mL, single-neck, round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]decan-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (12.8 mg, 0.032 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 22.5 mg, 0.096 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (30.6 mg, 0.160 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21.6 mg, 0.160 mmol), N-ethyl-N-isopropylpropan-2-amine (41.3 mg, 0.320 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (13.3 mg, 67.5%). LRMS (APCI pos): m/e 617 (M+1).