Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: CCCCCCOc1ccc2cc(C3(O)CCNCC3)ccc2c1
Product: CCCCCCOc1ccc2cc(C3(O)CCN(CCCOc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 32.3 %

Procedure:
Beginning with 0.257 gm (1.2 mMol) 1-(4-indolyloxy)-3-chloropropane and 0.400 gm (1.2 mMol) 4-hydroxy-4-(6-hexyloxynaphth-2-yl)piperidine, 0.194 gm (32%) of the title compound was recovered as a white solid by the procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1>[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cccc(C(=O)O)c1
Agent: [Pd]
Product: COc1cc(N)ccc1-c1cccc(C(=O)O)c1

Procedure:
The title compound can be prepared by palladium catalyzed hydrogenation of 2-methoxy-4-nitro-3′-biphenyl carboxylic acid.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.CCCCCC.[C:12]([N:15]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:14])[CH3:13].[Cl-].[NH4+]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[C:12]([N:15]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=[CH:1][CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:14])[CH3:13]
Reactant: [Li]CCCC
Reactant: CC(=O)N(Cc1ccccc1C=O)c1ccccc1Oc1ccccc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC=Cc1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 4.34 g of ethyltriphenyl-phosphonium bromide in 20 ml of tetrahydrofuran was added dropwise 6.63 ml of 1.63 M n-butyl lithium/hexane solution under a nitrogen stream, while keeping the temperature of the reaction solution at −15 to −10° C. The temperature of the reaction solution was gradually raised to room temperature, and after stirring at room temperature for 20 minutes, a solution of 1.01 g of N-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline in 10 ml of tetrahydrofuran was added dropwise, followed by further stirring for an hour. After addition of a saturated aqueous ammonium chloride solution, the reaction solution was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure to give 859 mg of N-acetyl-N-[2-(propen-1-yl)benzyl]-2-phenoxyaniline as an oil in a mixture of the geometrical isomers at a ratio of about 3:2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH2:23][CH3:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[CH2:23][CH3:24])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: CCc1ccncc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 3.4 %

Procedure:
Using the same reaction conditions as described in example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 600 mg, 2.739 mmol) was reacted with 3-bromo-4-ethyl-pyridine (512 mg, 2.739 mmol), 1,4-dioxane (10 mL), copper iodide (52 mg, 0.2739 mmol), trans-1,2-diamino cyclohexane (94.08 mg, 0.82 mmol) and potassium phosphate (1.74 mg, 8.2 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by preparative HPLC afforded 30 mg of the product (3.75% yield).
Reaction SMILES: C(OC(OCC)C[N:6]([C:16](=O)[CH3:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)C.[ClH:22].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:27][CH2:28][NH2:29].C(O)CCC>O>[ClH:22].[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([NH:6][CH2:16][CH:17]2[C:30]3[C:26](=[CH:25][C:24]([OH:23])=[C:32]([OH:33])[CH:31]=3)[CH2:27][CH2:28][NH:29]2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: CCOC(CN(C(C)=O)c1ccc([N+](=O)[O-])cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(NCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 84.2 %

Procedure:
A mixture of N-acetyl-p-nitroanilinoacetaldehyde diethyl acetal (1 g), 3,4-dihydroxyphenethylamine hydrochloride (1 g), n-butyl alcohol (10 ml) and water (1.5 ml) was refluxed for 7 hours. In the course of the reaction, the above-mentioned acetal (2.5 g) was added to the mixture, twice in 0.5 g portions and five times in 0.3 g portions, one every hour. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was pulverized by adding ether and the powder was collected by filtration, washed with ethyl acetate and water and dried to give 1-(p-nitroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1 g), mp 238° to 239° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[C:5]2[NH:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH:7]([CH3:17])[C:6]=2[CH:18]=1.NN>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]2[NH:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: CC(C)=CCN1CCNc2c(cc(Cl)cc2[N+](=O)[O-])C1C
Agent: [Ni]
Agent: NN
Solvent: CO
Product: CC(C)=CCN1CCNc2c(N)cc(Cl)cc2C1C
Yield: 100 %

Procedure:
To a solution of 1.34 parts of 7-chloro-2,3,4,5-tetrahydro-5-methyl-4-(3-methyl-2-butenyl)-9-nitro-1H-1,4-benzodiazepine (prepared as intermediate 11) in methanol there were added 0.49 parts of Raney nickel. To the resulting suspension there was added dropwise a solution of 1.09 parts of hydrazine in a small amount of methanol, at reflux temperature and under an Argon atmosphere. Refluxing was continued for 1½ hour. After cooling, the catalyst was filtered off and the filtrate was evaporated, yielding 1.3 parts (100%) of 7-chloro-2,3,4,5-tetrahydro-5-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine (interm. 19).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:29]=[C:30]=[S:31])[CH:27]=[CH2:28]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:30]([NH:29][CH2:26][CH:27]=[CH2:28])=[S:31])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: C=CCN=C=S
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: C=CCNC(=S)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 58 μl (2 molar equivalents) of allyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 90 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=69%) which was characterized as follows:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN(CC(O)c1csc(C(F)(F)F)n1)C(C)Cc1ccc(OCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.21 g (0.005 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl) ethanamine is dissolved in 10 ml of butan-2-one, and 0.5 ml of ethyl bromoacetate and 0.5 g of potassium carbonate are added, and the mixture is stirred at room temperature for 16 hours. The inorganic products are removed by filtration, and the solvent is removed by distillation. The remaining oil is purified on a silica gel column using toluene/ethyl acetate =85:15 as eluant. A colourless oil is obtained.
Reaction SMILES: C(OC(=O)[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7])C.[BrH:15].[Br:16]Br>>[BrH:15].[Br:15][CH:5]([Br:16])[C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CCOC(=O)CC(=O)c1cccnc1
Reactant: BrBr
Agent: Br
Product: O=C(c1cccnc1)C(Br)Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
3-(3-Pyridyl)-3-oxopropionic acid ethyl ester (1.95 g, 10.2 mmol) was added dropwise to 47% aqueous HBr solution (3.86 g) under ice-cooling. Bromine (2.2 g, 1.2 equivalent amount relative to 3-(3-pyridyl)-3-oxopropionic acid ethyl ester) was added dropwise at not more than 10° C. After stirring for 30 min, iced-water bath was removed and water (2 ml) and 47% aqueous HBr solution (4 ml) were added. The mixture was stirred at room temperature for 30 min. Furthermore, bromine (2.2 g, 1.2 equivalent amount relative to 3-(3-pyridyl)-3-oxopropionic acid ethyl ester) was added dropwise and the mixture was stirred at 65-70° C. After cooling to room temperature, the reaction mixture was filtrated to give 3.73 g of the titled compound (yield 95.2%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1cccc(CBr)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2cccc(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-3-fluorobenzene (0.41 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.82 g, 63%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[N:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[N:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cnc(Cn3ncc(N)n3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cnc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][CH2:11][C:10]2[N:9]=[C:8]([CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:7]=[CH:6][C:5]1=2)=[N+]=[N-].CCOC(C)=O.CO>CCOC(C)=O.CO.[Pd]>[Si:17]([O:16][CH2:15][CH2:14][C:8]1[N:7]=[CH:6][C:5]2[CH:4]([NH2:1])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A suspension of 80 mg of Pd/C (10% w/w) in a solution of 5-azido-2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazoline (800 mg, 1.75 mmol) in 30 mL of EtOAc was stirred under H2 atmosphere overnight. The reaction mixture was then directly submitted to flash chomatograph (SiO2, EtOAc to EtOAc/MeOH=100:15 to EtOAc/2M NH3 in MeOH=2:1) to give the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][C:11]2[N:12]=[C:13]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][C:11]2[N:12]=[C:13]([C:24]([CH3:25])([CH3:27])[CH3:26])[N:14]=[C:15]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C(C)(C)C)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2nc(C(C)(C)C)nc(-c3ccc(F)cc3)c2C1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To the product from Step B (0.17 g, 0.39 mmol) was added 4-fluorophenylboronic acid (0.082 g, 0.586 mmol), K3PO4 (0.124 g, 0.584 mmol), Pd(Cl)2dppf.CH2Cl2 (0.018 g, 0.022 mmol) and dppf (0.008 g, 0.014 mmol). The mixture was evacuated with N2, dioxane (4 mL) was added and the mixture was heated at reflux for 2 h. After cooling to room temperature (rt), the mixture was diluted with Et2O, filtered through a small SiO2 plug, and the filtrate was concentrated. The resulting residue was purified via SiO2 chromatography (5-30% EtOAc/hexanes) to give 0.134 g (89%) of the title compound. MS (ESI): exact mass calcd. for C22H28FN3O2, 385.22; m/z found, 386.4 [M+H]+. 1H NMR (CDCl3): 7.60 (dd, J=5.4, 8.8, 2H), 7.17-7.14 (m, 2H), 4.59 (s, 2H), 3.76 (t, J=6.1, 2H), 3.09 (t, J=6.1, 2H), 1.44 (s, 9H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][C@@H:18]3[C:33]([O:35][CH3:36])=[O:34])=[O:16])[CH2:11][CH2:10]2)=[C:5]([CH3:37])[CH:4]=1)#[N:2].CO>[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[C:33]([O:35][CH3:36])=[O:34])=[O:16])[CH2:11][CH2:10]2)=[C:5]([CH3:37])[CH:4]=1)#[N:2]
Reactant: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl 3-methyl(3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-1,3-dicarboxylate (0.5265 g, 0.001043 mol) in methanol (11.00 mL, 0.2716 mol) was added 10% palladium (93.9 mg, 0.0000883 mol) on carbon at room temp. The reaction mixture was stirred under hydrogen balloon at 1 atm pressure overnight. After overnight stirring reaction mixture was filtered and concentrated to give the product in quantitative yield. MS (ESI): (M+H)+=371.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]=2[C:11](O)=[O:12])[CH:7]=1.O[N:21]1[C:25]2N=CC=CC=2N=N1.Cl.CN.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(OC(=O)C)C.CN(C)C=O.ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]=2[C:11]([NH:21][CH3:25])=[O:12])[CH:7]=1
Reactant: O=C(O)c1c(-c2ccccc2)nn2cc(I)ccc12
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccccc2)nn2cc(I)ccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.8 %

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stir bar was charged 6-iodo-2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid (200 mg, 0.549 mmol), 1-Hydroxy-7-azabenzotriazole (74.8 mg, 0.549 mmol), methylamine hydrochloride (55.6 mg, 0.824 mmol), diisopropylethylamine (671 μL, 3.84 mmol), dichloromethane (5000 μL) and dimethylforamide (500 μL). To this yellow solution 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (147 mg, 0.769 mmol) was added. The reaction was stirred at room temperature for six hours and diluted with ethylacetate (200 mL). The organic portion was washed 5× with 0.5N hydrochloric acid, 1× saturated sodium bicarbonate and 2× brine. The organic portion was dried over magnesium sulfate. The solvent was removed by rotory evaporation. The residue was place under vacuum overnight to give a white solid (130 mg, 90%). 1H NMR (500 MHz, MeOD) δ ppm 2.87 (m, 3H) 7.51 (m, 3H) 7.63 (dd, J=9.31, 1.37 Hz, 1H) 7.76 (m, 3H) 8.94 (s, 1H). LCMS: 1.8 minutes, M+1=378.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[Cl:50][C:51]1[CH:52]=[C:53]([CH:63]=[CH:64][C:65]=1[NH:66][C:67]1[N:72]=[C:71]([NH:73][C:74]2[C:75]([C:89](=[O:92])[NH:90][CH3:91])=[N:76][C:77]([C:80]3[CH:81]=[N:82][N:83]([CH2:85][CH2:86][CH2:87][OH:88])[CH:84]=3)=[CH:78][CH:79]=2)[C:70]([C:93]([F:96])([F:95])[F:94])=[CH:69][N:68]=1)[CH2:54][P:55](=[O:62])([O:59]CC)[O:56][CH2:57][CH3:58]>>[Cl:50][C:51]1[CH:52]=[C:53]([CH:63]=[CH:64][C:65]=1[NH:66][C:67]1[N:72]=[C:71]([NH:73][C:74]2[C:75]([C:89](=[O:92])[NH:90][CH3:91])=[N:76][C:77]([C:80]3[CH:81]=[N:82][N:83]([CH2:85][CH2:86][CH2:87][OH:88])[CH:84]=3)=[CH:78][CH:79]=2)[C:70]([C:93]([F:96])([F:94])[F:95])=[CH:69][N:68]=1)[CH2:54][P:55](=[O:59])([OH:62])[O:56][CH2:57][CH3:58]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(Cl)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(Cl)c1
Yield: 99.8 %

Procedure:
Prepared analogously to Compound 3A using diethyl (3-chloro-4-{[4-({6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 24B, 176 mg, 253 μmol) to afford 169 mg of the title compound (100%). 1H NMR (400 MHz, CD3OD) δ=8.85-8.93 (m, 1H), 8.55 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.68 (d, J=9.1 Hz, 1H), 7.52-7.59 (m, 2H), 7.34 (d, J=8.01 Hz, 1H), 4.31 (t, J=6.8 Hz, 2H), 3.88 (t, J=7.1 Hz, 2H), 3.58 (t, J=6.2 Hz, 2H), 3.04 (d, J=21.0 Hz, 2H), 2.98 (s, 3H), 2.11 (t, J=6.3 Hz, 2H), 1.14 (t, J=7.1 Hz, 3H). MS (ESI): m/z=669.66 [M+H]+. UPLC: tR=1.17 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH2:33])([CH2:23][C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:19]([O:21]C)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CSC1C=CC(B(O)O)=CC=1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]([NH2:33])([CH2:23][C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:19]([OH:21])=[O:20])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(N)(CC#CCN1CCOCC1)S(=O)(=O)c1ccc(-c2ccc(SC)cc2)cc1
Agent: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2ccc(S(=O)(=O)C(N)(CC#CCN3CCOCC3)C(=O)O)cc2)cc1

Procedure:
Methyl 2-{[4′-Methylthio-(1,1′-biphenyl)-4-yl]-sulfonyl}-amino-6-morpholinohex-4-ynoate: The starting sulfonamide 34a (500 mg, 1.02 mmol) is coupled to 4-methylthiophenyl-boronic acid (257 mg, 1.53 mmol) as described for compound 32a to give the title compound as a light orange solid.
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[CH3:20][CH2:21][O:22][C:23]([CH:25]1[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26]1)=[O:24].Cl.C(N(C(C)C)CC)(C)C.[F:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1>>[F:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([N:27]2[CH2:28][CH2:29][C:30](=[O:31])[CH:25]([C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:26]2)=[O:48])=[CH:45][CH:44]=1
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CCC1=O
Yield: 84.4 %

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 4-piperidone-3-carboxylate hydrochloride (200.4 mg; 0.97 mmol), diisopropylethylamine (360 μl; 2.08 mmol) and 4-fluorobenzoyl chloride (114 μl; 0.97 mmol), giving ethyl 1-(4-fluorobenzoyl)4-oxo-3-piperidinecarboxylate (240.2 mg) as a thick, light yellow oil without further purification. MS m/z (positive ion) 348 (25), 316 (M+Na+; 75), 294 (MH+; 100).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][C:24](F)=[CH:25][C:19]=4[C:18]=3[CH3:27])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[OH-].[K+].CN(C)CC[OH:34]>CS(C)=O.C(OCC)(=O)C.O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][C:24]([OH:34])=[CH:25][C:19]=4[C:18]=3[CH3:27])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CN(C)CCO
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(O)cc4c3C)c(C)nc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 25.1 %

Procedure:
In an oven dried, nitrogen purged pressure tube, 0.040 g (0.105 mmol) of 8-(1-ethyl-propyl)-3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine, 0.012 g (0.21 mmol) of KOH, and 0.019 g (0.210 mmol) of N,N-dimethylethanolamine are combined in 1 mL of dry DMSO and heated at 90° C. After approximately 24 hours, the reaction mixture is diluted with 20 mL of ethyl acetate and 20 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using Hexane/Ethyl Acetate. The product containing fractions are combined to obtain 0.010 g of the title compound, 25% yield. MS, ES+=380.1 (M+1); 1H NMR (DMSO-d6)=9.518 (s, 1H); 7.760-7.730 (s, 1H); 7.129 (s, 1H); 6.980 (s, 1H); 3.150-3.050 (m, 1H); 2.421 (s, 3H); 2.336 (s, 3H); 2.103 (s, 3H); 1.850-1.760 (m, 4H); 0.789-0.753 (m, 6H) ppm.