Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([F:19])[CH:18]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[C:17]([F:19])[CH:18]=[C:13]([Cl:12])[CH:14]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Fc1cc(Cl)cc(-c2cc(Cl)c3c(n2)CCC3)c1
Yield: 59.7 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.250 g, 1.33 mmol) was reacted with (3-chloro-5-fluorophenyl)boronic acid (0.301 g, 2.07 mmol), to afford the title compound (0.224 g, 90%) as a white solid. MW=282.14. 1H NMR (CD3OD, 300 MHz) δ 7.87-7.84 (m, 1H), 7.72-7.65 (m, 2H), 7.30-7.21 (m, 1H), 3.17-3.00 (m, 4H), 2.21 (quin, J=7.6 Hz, 2H); APCI MS m/z 282 [M+H]+.
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[O:9]([CH2:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:30][CH:29]=1)[Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:54]([N:58]([CH2:69][CH2:70][CH2:71][CH3:72])[C:59]1[CH:66]=[CH:65][C:62]([CH:63]=O)=[C:61]([O:67][CH3:68])[CH:60]=1)[CH2:55][CH2:56][CH3:57].O>O1CCCC1.C(OCC)(=O)C>[CH2:54]([N:58]([CH2:69][CH2:70][CH2:71][CH3:72])[C:59]1[CH:66]=[CH:65][C:62]([CH:63]=[CH:32][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:53][CH:52]=2)=[C:61]([O:67][CH3:68])[CH:60]=1)[CH2:55][CH2:56][CH3:57]
Reactant: CC(C)(C)[Si](OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)c(OC)c1
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
In a stream of argon, to 35 ml of tetrahydrofuran was added 3.33 g of phenyllithium (19% solution in dibutylether) (7.53 mmol), and 4.8 g (6.84 mmol) of 4-(tert-butyldiphenylsiloxymethyl)benzyltriphenylphosphonium bromide was added thereto under ice cooling. Next, 1.8 g (6.838 mmol) of 4-dibutylamino-2-methoxybenzaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. Ethyl acetate/hexane (5/1) was added to the residue and the precipitate was filtered off. The filtrate was reconcentrated and the residue was purified by silica gel column chromatography to give 3.92 g of a yellow liquid (yield: 94.7%).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][C:25]([O:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])=[O:26])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)C.CO.[OH-].[Li+]>O>[CH3:23][C:20]1[C:19]([NH:24][C:25]([O:27][C@@H:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:29])=[O:26])=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:36])=[O:3])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)[O:22][N:21]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of {4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester (24 g, 49 mmol) in 3:1 MeOH:H2O (300 mL) was added lithium hydroxide (8.3 g, 198 mmol), and the reaction was stirred at room temperature overnight. The mixture was acidified and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound. Mass spec. data (M+H)=457.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(NC(C)C)(C)C.[I-].[Na+]>CN(C)C=O.O>[C:4]1([CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][CH:23]([NH:22][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:24][CH2:25]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1cccc2ccccc12
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(CCc2cccc3ccccc23)CC1)c1ccccc1
Temperature: 70 °C
Yield: 65.6 %

Procedure:
1-(2-Bromoethyl)naphthalene (3.0 g.) was added to a solution of 4-benzamidopiperidine (3.0 g.), di-isopropylamine (4 ml.) and a trace of sodium iodide in dimethylformamide (10 ml.). The mixture was heated at 70° C overnight, then poured into water and extracted with methylene chloride. The washed and dried extracts were evaporated and the residue was recrystallised from benzene to give the title compound (3.0 g.), m.p. 160°-162° C. (Found: C, 80.5; H, 7.4; N, 7.5 C24H26N2O requires C, 80.4; H, 7.3; N, 7.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([O:17][C:18](=[O:31])[CH2:19][O:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:31])[CH2:19][O:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CONCc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CC(C)(C)OC(=O)CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 49 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with [N-(3,4-dichlorobenzyl)aminooxy]-acetic acid tert-butyl ester as described in the preparation of compound 1-A gave the title amide as white crystals (49% yield): mp 127-129° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.51 (9H, s, t-Bu), 1.78 (6H, s, CH3), 4.38 (2H, s, CH2), 4.90 (2H, s, CH2), 6.49 (1H, s, CH), 7.28 (1H, dd, J=2.5 Hz and J=8.0 Hz, aromatic), 7.41 (1H, d, J=8.0 Hz, aromatic), 7.53 (1H, d, J=2.5 Hz, aromatic). Anal. calcd for C20H23Cl2NO7: C, 52.19; H, 5.04; N, 3.04. Found: C, 52.25; H, 5.11; N, 2.93.
Reaction SMILES: NC(NC1C=C(C(NCC(NC(C2C=C(Cl)C=C(Cl)C=2)CC(OCC)=O)=O)=O)C=CC=1)=NC#N.[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]([NH:52][C:53](=[O:78])[CH2:54][NH:55][C:56]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:65]([NH:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])=[N:66][C:67]([O:69][CH2:70][CH3:71])=[O:68])[CH:59]=2)=[O:57])[CH2:44][C:45]([O:47]C(C)(C)C)=[O:46])[CH:39]=[C:40]([Cl:42])[CH:41]=1>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]([NH:52][C:53](=[O:78])[CH2:54][NH:55][C:56]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:65]([NH:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])=[N:66][C:67]([O:69][CH2:70][CH3:71])=[O:68])[CH:59]=2)=[O:57])[CH2:44][C:45]([OH:47])=[O:46])[CH:39]=[C:40]([Cl:42])[CH:41]=1
Reactant: CCOC(=O)N=C(NC(=O)OCC)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)OC(C)(C)C)c2cc(Cl)cc(Cl)c2)c1
Agent: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(N)=NC#N)c1)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)N=C(NC(=O)OCC)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2cc(Cl)cc(Cl)c2)c1

Procedure:
The title compound was prepared following the procedure described in Example 160, replacing the compound of Example 159 with the compound of Example 165. The title compound was obtained as a white solid.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7](OCC)=[O:8])[CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3]1)=[O:8])[NH2:21]
Reactant: NN
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Temperature: 25 °C

Procedure:
10.0 g (38.9 mmol) of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate were initially charged in 35 ml of ethanol, and 3.8 ml (3.90 g, 78 mmol) of hydrazine hydrate were added with stirring. The mixture was stirred at reflux for 9 h. The reaction mixture was cooled to RT, 1.9 ml (39 mmol) of hydrazine hydrate were added and the reaction solution was stirred at reflux for another 24 h. The solvent was concentrated, ethanol (50 ml) was added and the mixture was concentrated again. Diethyl ether (150 ml) was added, and the mixture was stirred in an ultrasonic bath for 5 min. The product was filtered off and dried. This gave 9.20 g (97% of theory) of the product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2[N:14]=[C:15](F)[CH:16]=[CH:17][C:11]=2[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[CH2:1]([N:8]1[CH2:13][C:12]2[N:14]=[C:15]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=3[O:27][CH3:26])[CH:16]=[CH:17][C:11]=2[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)Cc2nc(F)ccc2N1c1ccccc1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNc2ccc3c(n2)CN(Cc2ccccc2)C(=O)N3c2ccccc2)c(OC)c1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
A mixture of 3-benzyl-6-fluoro-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (112 mg, 0.34 mmol, 1.0 equiv) and 2,4-dimethoxybenzyl-amine (1.0 mL, 6.7 mmol, 20 equiv) was heated in the microwave reactor at 150° C. for 2 h. The crude reaction mixture was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-50%) to afford 3-benzyl-6-(2,4-dimethoxy-benzylamino)-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (66 mg). MS: [M+H]+=481.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.[CH:13]([N:16](CC)C(C)C)(C)C.S(Cl)(Cl)=O.[C-]#N.[Na+]>C1COCC1.CC(OC)(C)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:13]#[N:16])=[CH:5][CH:4]=1
Reactant: OCc1ccc(C(F)(F)F)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: N#CCc1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of (6-trifluoromethyl-pyridin-3-yl)-methanol (4.93 g, 27.8 mmol) in THF (50 mL) were added N,N-diisopropyl ethyl amine (5.7 mL, 33 mmol) and 4-dimethyl-aminopyridine (17 mg, 0.14 mmol). After cooling to 0° C. thionyl chloride (4.8 mL, 56 mmol) was added dropwise over a period of 10 min. After stirring for 30 min. at 0° C., the ice bath was replaced with a water bath and stirred for 2 h at ambient temperature. The resulting brown reaction mixture was concentrated in vacuo, diluted with TBME (50 mL) and cooled to 0° C. before aqueous NaHCO3 (1M, 100 mL) was added. The mixture was stirred for 30 min., the aqueous layers were extracted with TBME (50 mL) and the combined organic layers were washed with aqueous NaHCO3 (1M, 50 mL) and brine (50 mL). Drying over sodium sulphate was followed by concentration. The resulting oil (6.44 g) was dissolved in DMSO (15 mL) and sodium cyanide (1.36 g, 27.8 mmol) was added. The resulting dark reaction mixture was stirred for 18 h at ambient temperature under a nitrogen atmosphere. It was diluted with TBME (50 mL) and treated with ice (30 g) and water (50 mL). The aqueous layer was separated and extracted with TBME (50 mL). The organic layers were washed twice with water (50 mL) and brine (30 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 50:50) afforded the title compound (3.59 g, 59%) as a light brown oil. MS m/e: 185.3 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[CH2:10][OH:11].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([O:11][CH2:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[Br:9])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OCc1c(Br)cc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cc(F)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
To a solution of 101i (20 g, 71 mmol) in CH2Cl2 (500 mL) at 0° C. was added pyridine (8.4 g, 107 mmol) and acetyl chloride (8.3 g, 107 mmol). The mixture was stirred at room temperature for 5 h. TLC showed the start material disappeared. The reaction was evaporated in vacuum and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 101j as a white solid (20 g, 87%). MS: [M−Oac]+ 267. 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J=7.5, 2H), 5.38 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[CH3:23][C@H:24]1[O:29][C@@H:28]([CH3:30])[CH2:27][NH:26][CH2:25]1.CC(O)C.O1CCOCC1>C(OCC)(=O)C.[Cl-].[Na+].O>[CH:10]([N:8]1[CH2:9][CH:6]([N:26]2[CH2:25][C@H:24]([CH3:23])[O:29][C@H:28]([CH3:30])[CH2:27]2)[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: C[C@@H]1CN(C2CN(C(c3ccccc3)c3ccccc3)C2)C[C@H](C)O1
Reaction time: 4 h
Yield: 64.6 %

Procedure:
3-Methanesulfonyloxy-1-benzhydrylazetidine (3.84 g, 12.1 mmol) and cis-2,6-dimethylmorpholine (6.97 mL, 60.5 mmol) were introduced into a screw vial, and IPA (10 mL) and dioxane (3 mL) were added thereto. The mixture was left to stand for 4 hours at 100° C. The reaction liquor was diluted with ethyl acetate, and saturated brine was added thereto. The mixture was partitioned. The obtained organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by column chromatography using silica gel (Flash Chromatography System from Biotage AB, column size: 40M, hexane/ethyl acetate=9:1 to 1:1), to obtain the title compound (2.63 g, 65%) as an oily matter.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.[N:17]1([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[C:29](=[O:32])[O:30][CH2:31][C:27]=3[CH:26]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([N:20]2[CH2:21][CH2:22][N:17]([CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:28]4[C:29](=[O:32])[O:30][CH2:31][C:27]=4[CH:26]=3)[CH2:18][CH2:19]2)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)c(F)c1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)c(F)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-fluoro-4-(1H-tetrazol-1-yl)phenyl]acetic acid (0.68 mmol) in 10 mL of anhydrous DCM was added 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (191 mg, 0.68 mmol), EDC (200 mg, 1.01 mmol), HOBt (136 mg, 1.01 mmol), TEA (341 mg, 3.38 mmol) was stirred at ambient temperature overnight. The mixture was added DCM, washed with brine, the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC to give the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.84 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.31˜737 (m, 3H), 7.11˜7.19 (m, 2H), 5.29 (s, 2H), 3.59 (s, 2H), 3.49˜3.52 (m, 2H), 3.37˜3.4 (m, 2H), 2.89˜2.93 (m, 2H), 2.64˜2.68 (m, 2H), 2.4˜2.45 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]([CH2:16][CH:17]=[CH2:18])[CH3:15].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:12][N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH:14]([CH2:16]/[CH:17]=[CH:18]/[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1)[CH3:15]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cncc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 119 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-bromo-3-isopropoxypyridine (847.0 mg, 3.92 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (784.7 mg, 3.94 mmol), palladium(II) acetate (9.0 mg, 0.04 mmol), tri-o-tolylphosphine (50.0 mg, 0.16 mmol), triethylamine (0.73 g, 7.21 mmol), and anhydrous acetonitrile (2 mL) was stirred and heated under reflux at 80° C. for 20 h. The mixture, containing solids was cooled, diluted with water (10 mL), and extracted with CHCl3 (3×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give an oily residue (1.56 g). The crude product was purified by column chromatography on silica gel, eluting with 25→40% (v/v) ethyl acetate in hexane. Selected fractions containing the product were combined and concentrated to give 1.15 g (87.8%) of a light-amber oil.
Reaction SMILES: O.[OH-].[Li+].C[CH:5]([CH2:9][CH2:10][S:11][C:12]1[N:13]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[N:14]=[C:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]2[CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]([OH:8])=[O:7]>O1CCCC1.O>[CH3:22][N:18]1[C:19](=[O:21])[C:20]2=[C:12]([S:11][CH2:10][CH2:9][CH2:5][C:6]([OH:8])=[O:7])[N:13]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[N:14]=[C:15]2[N:16]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:17]1=[O:23]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCC(C)C(=O)O)n(Cc3cccc4ccccc34)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)nc21
Yield: 53.5 %

Procedure:
Lithium hydroxide monohydrate (80 mg) was added to a solution of methyl 4-[(4,5,6,7-tetrahydro-5-methyl-7-{2-methylpropyl}-2-{1-naphthalenylmethyl}-4,6-dioxo-2H-pyrazolo[3,4-d]pyrimidin-3-yl)thio]butanoic acid (250 mg) in tetrahydrofuran (20 ml) and water was then added to give a homogeneous solution. After 18 hours the reaction mixture was partitioned between ether and 2 M sodium hydroxide. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate which was then dried over magnesium sulfate. The organic phase was concentrated in vacuo and recrystallised from cyclohexane:ethyl acetate to give the title compound (130 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:16])[CH:10]=[C:9]([Cl:17])[N:8]=1>C1COCC1>[Cl:17][C:9]1[N:8]=[C:7]([S:5][CH2:3][CH3:4])[C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:16])[CH:10]=1
Reactant: CCS
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1nc(Cl)cc(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
6.1 g (153 mmol, 60% w/w in mineral oil) NaH were dissolved in THF (90 ml) at 0° C. At this temperature 3.4 g (54.7 mmol) ethane thiol were added. After stirring for 15 min at 0° C., 12.4 g (60.2 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid were added portionwise. The RM was allowed to warm to RT and stirring was continued at RT for 16 h. Then the reaction was quenched with a 2M aq. HCl and diluted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Crystallisation (DCM/hexane) of the residue yielded 12.0 g (51.7 mmol, 95%) 6-chloro-2-ethylsulfanyl-4-methyl-pyridine-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:38][CH2:37][O:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:38][CH2:37][O:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCOC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCOC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
795 mg (1.3 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoyl}amino)benzoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 2. Yield: 405 mg (59% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20](C)=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.N1([CH2:38][C:39]2[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=2)[NH2:42])CCCC1.Cl>CC(O)C>[NH2:3][CH:4]1[CH2:38][C:39]2[CH:40]=[C:41]([NH:42][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:22]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:20]=[CH:19][CH:18]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:43]=[CH:44][C:45]=2[CH2:6][CH2:5]1
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: Cc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Agent: Cl
Solvent: CC(C)O
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 44.5 %

Procedure:
N-{5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-methylphenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mmol), 3-(1-pyrrolidinylmethyl)aniline (78 mg, 0.44 mmol) and catalytic conc. HCl in iPrOH (4 mL) were heated in a microwave at 180° C. for 10 min. The reaction was concentrated and the residue was dissolved in DCM. The organic solution was washed with saturated NaHCO3 (aq) and water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by column chromatography. Fractions containing pure product were concentrated, taken up in MeOH and neutralized with MP-carbonate. The mixture was filtered and the filtered concentrated and triturated with DCM and hexanes to give the title compound (28 mg, 21%). 1H NMR (400 MHz, d6-DMSO) δ 9.62 (s, 1H), 9.50 (s, 1H), 8.80 (d, J=6.8 Hz, 1H), 8.50 (d, J=9.2 Hz, 1H), 8.21 (d, J=5.6 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.45-7.41 (m, 1H), 7.36 (m, 1H), 7.32-7.28 (m, 2H), 7.16 (t, J=7.8 Hz, 1H), 7.11-7.07 (m, 1H), 6.98-6.95 (m, 2H), 6.87 (d, J=7.2 Hz, 1H), 6.50 (d, J=5.6 Hz, 1H), 3.91 (s, 2H), 3.50 (s, 2H), 2.39 (m, 4H), 2.26 (s, 3H), 1.65-1.64 (m, 4H) ppm. ES-LC/MS m/z=600 [M+H]+.